Functionalized ZIF-8 as a versatile platform for drug delivery and cancer therapy: strategies, challenges and prospects

Abstract

This review discusses the functionalization strategies of ZIF-8 and challenges and future developments in ZIF-8-based platforms for drug delivery and cancer therapy. We systematically evaluate a series of innovative ZIF-8 functionalization methods, including atomic doping, introduction of targeting molecules, and biomimetic mineralization technology, to achieve precise drug release. These functionalization strategies significantly enhance the targeted delivery and controlled release properties of ZIF-8, broaden the diversity of drug delivery systems, maximize therapeutic effects, and minimize systemic toxicity. In addition, this review explores the important role of ZIF-8 in tumor therapy. Its ability to encapsulate multiple therapeutic agents and its responsiveness to the tumor microenvironment significantly improve the therapeutic effect and reduce the side effects of traditional treatments. By integrating multiple therapeutic agents and performing surface modification, ZIF-8-based platforms may provide personalized and efficient treatment options for drug-resistant or recurrent cancers. This review also comprehensively discusses the synthesis methods, drug loading capacity, and potential clinical applications of ZIF-8, emphasizing the need to optimize its large-scale production and reproducibility. In addition, further studies on the long-term biocompatibility and biodegradability of ZIF-8-based systems are essential to ensure their safety in long-term treatment. In summary, this review highlights the structural advantages and significant therapeutic potential of ZIF-8 and calls for the transition of ZIF-8 from laboratory research to clinical application to provide more targeted, efficient, and friendly cancer treatment options.

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Wenyue Gao

Wenyue Gao received her BS degree in Pharmacy from Xi'an Medical University, Xi'an, China, in 2023. She is currently pursuing an MS degree in Pharmacy with Associate Professor Cuijuan Wang at Southwest Jiaotong University (SWJTU) in Chengdu, China. Her research interests focus on the applications of MOFs in antibacterial and wound healing therapies.

Xinping Han

Xinping Han received her bachelor's degree from the Shandong University of Technology in 2021. She is currently pursuing her master's degree at Southwest Jiaotong University under the supervision of Associate Professor Cuijuan Wang. Her research interests focus on MOFs for bacterial detection and antimicrobial therapy to target the problem of bacterial infection.

Ling Li

Ling Li received her Bachelor's degree from Zunyi Medical University in 2022. She is currently a graduate student at the School of Life Science and Engineering, Southwest Jiaotong University. Her research primarily focuses on utilizing MOF and COF materials for the photocatalytic reduction of carbon dioxide, aiming to achieve high-value-added CO2 conversion and mitigate the greenhouse effect.

Yan Xu

Yan Xu received her Bachelor's degree from the Sichuan University of Science & Engineering in 2023. She is now studying for her master's degree with Associate Professor Cuijuan Wang at Southwest Jiaotong University. Her research field is MOF-based nanomaterials for applications in electrocatalysis.

Zhu Gao

Zhu Gao received his PhD in Chemistry from Central South University in 2024 and is currently employed as an instructor at Southwest Jiaotong University for Chemistry. In particular, he studies metal–organic frameworks and functional porous polymers for photocatalytic environmental and energy applications.

Cuijuan Wang

Cuijuan Wang obtained her PhD in 2008 from the Northwest University. She is currently an Associate Professor in the School of Chemistry at Southwest Jiaotong University. Her research interests are in the synthesis and functionalized modification of metal–organic framework materials for photocatalysis, electrocatalysis, slow drug release, and biological applications.

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1. Introduction

For most drugs, there are problems such as poor water solubility, poor chemical stability, and poor targeting. Therefore, to improve the efficacy of drugs, it is usually necessary to wrap the drugs with carriers for protection and delivery. The main purpose of drug delivery is to ensure that the drug can accurately and safely reach the site or target tissue that needs treatment to exert its therapeutic effect. The field of drug delivery is constantly seeking innovative approaches to improve therapeutic efficacy and reduce adverse effects. With the development of nanotechnology, nanocarriers have attracted much attention as effective tools for drug delivery. These carriers can optimize the bioavailability of drugs, enhance targeting and reduce toxicity, opening up new ways to treat diseases. Metal–organic framework (MOF) materials are some of them. They are three-dimensional porous coordination polymers composed of metal ion or metal cluster nodes as secondary building units and organic materials as ligands and they self-assemble through coordination interactions.¹ Zeolitic imidazolate framework-8 (ZIF-8) is the most representative one, consisting of Zn²⁺ and 2-methylimidazole (2-MIM). It inherits the structural advantages of traditional MOFs while overcoming their shortcomings. It has a rich pore structure, high specific surface area, structural diversity, easy modification capability, good biocompatibility, high drug loading rate and pH responsiveness. These properties have led to its wider application in biomedical fields such as drug delivery,² biosensing,³ and photothermal therapy (PTT)⁴ and photodynamic therapy (PDT).⁵ In addition, there are many synthesis methods for ZIF-8, which mainly include room temperature solution reaction methods,⁶ solvothermal methods,^7,8 hydrothermal synthesis methods,^9,10 microfluidic synthesis methods,^11–13 mechanochemical methods,¹⁴etc.Table 1 shows the advantages of different synthesis methods of ZIF-8 and their shortcomings. These methods have their own advantages and applicable scenarios, but in general, they all achieve the synthesis of ZIF-8 crystals by controlling the reaction conditions between metal ions and organic ligands. In practical applications, the reaction conditions can be adjusted as needed to control the morphology, size, and properties of ZIF-8. The most commonly used method for synthesis of ZIF-8 is room temperature synthesis, which involves stirring the metal ion solution and the ligand solution at room temperature. Therefore, using this characteristic, drugs can be introduced into the precursor and solution during the synthesis process to achieve one-step drug loading. ZIF-8 also has excellent stability and can protect the drug from being damaged by high temperature environments after being wrapped. In addition, ZIF-8 is pH-responsive and will disintegrate in an acidic environment. Many studies use ZIF-8 as a drug carrier, using its characteristics of destroying and slowly releasing drugs inside the pores in an acidic environment to achieve targeted therapy for tumors. Significant progress has been made especially in the delivery of anti-tumor drugs. The Zn²⁺ released after the disintegration of ZIF-8 itself also has a bactericidal effect and has excellent applications in the delivery of antibacterial drugs. Taken together, these distinct features make ZIF-8 an attractive drug encapsulation and delivery vehicle. It can achieve the following drug delivery goals: improved therapeutic efficacy, reduced side effects, enhanced drug stability, and improved patient convenience.

Table 1 The advantages and disadvantages of ZIF-8 synthesis methods

Method	Advantages	Disadvantages
Room temperature solution reaction method	Simple, environmentally friendly, and a fast synthesis rate	Small crystal size and specific surface area and limited production batch
Solvothermal method	Controlled crystal size and the crystal structure integrity	High energy consumption and long reaction time
Hydrothermal method	High degree of crystallinity, green and environmental protection	Slow growth rate and the crystal morphology is difficult to control
Microfluidic method	Fast, energy conservation, and crystal quality	High equipment cost, difficult to control reaction conditions, limited choice of reaction substances
Mechanochemical method	No solvent required and energy efficient	Produce local high temperature or high pressure and product purity is difficult to guarantee

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In addition, ZIF-8 also has noteworthy advantages in tumor treatment. As we all know, cancer is an extremely destructive and harmful disease that poses a serious threat to human health and life. Traditional treatment methods mainly include surgery, chemotherapy, and radiotherapy.¹⁵ However, they have some side effects including but not limited to nausea, vomiting, hair loss, immune system damage, and other adverse reactions. With the continuous advancement of medical technology, more and more new therapies and comprehensive treatment methods, such as immunotherapy (IMT),^16,17 gene therapy (GT),¹⁸ chemodynamic therapy (CDT),^19–21 phototherapy,^22–25 and starvation therapy (ST),^26–28 are being developed and applied in cancer treatment, to improve treatment effects and reduce side effects. However, these methods still face severe challenges in tumor treatment. For example, CDT is limited by insufficient endogenous hydrogen peroxide (H₂O₂) and PDT faces the problem of poor photosensitizer (PS) stability. In recent years, with extensive research on ZIF-8, research on nanoplatforms based on ZIF-8 has revealed its profound impact in the field of tumor treatment, and its design and application prospects are huge. ZIF-8 has the following significant advantages in tumor treatment: (i) as a metal–organic framework, ZIF-8 has a variety of metal ions/ion clusters and bridging ligand combinations, providing a wide range of options for building multifunctional nanoplatforms. Personalized tumor treatment plans can be achieved. (ii) ZIF-8 has high porosity and large specific surface area and can efficiently load chemical drugs, ions, phototherapeutic agents, proteins, enzymes, antigens and other functional agents, thereby improving the therapeutic effect and reducing the occurrence of adverse reactions. (iii) Through the coordination of metal nodes and surface modification of ZIF-8, the targeting effect, biocompatibility and stimulus responsiveness during treatment can be improved. (iv) The degradable properties triggered by the tumor microenvironment (TME) promote the efficient excretion of ZIF-8, indicating that the ZIF-8-based nanoplatforms have great potential in tumor treatment using different therapeutic approaches, providing a more promising, effective, and safer solution for tumor treatment.

So far, there have been many review papers introducing the application of ZIF-8 in cancer treatment. The review written by Shu et al. focused on the synthesis strategy of ZIF-8 as a cancer therapeutic carrier and functionalized material and its significant effect in PDT and PTT, without in-depth discussion of its cancer inhibition mechanisms.²⁹ Our review not only details the mechanisms of tumor suppression by various therapies but also discusses how these therapies work. In addition, we review the comprehensive application of tumor diagnosis and the application of multiple therapies in coordinated tumor treatment. The review written by Gao et al. revealed that ZIF-8 is an ideal nanoplatform for loading chemotherapy drugs, PSs, photothermal agents and proteins, but lacks a detailed introduction to specific treatment procedures such as immunotherapy.³⁰ Our review not only considers important procedures in cancer treatment, but also discusses these procedures in detail in different sections and integrates them into theranostics and collaborative therapy.

In terms of drug delivery, the review written by Wang et al. explored recent advances in biomimetic ZIF-8 nanoparticles for drug delivery,³¹ while folic acid-conjugated ZIF-8 is the main focus of the review written by Oryani et al.³² However, our review article first provides a comprehensive summary and comparison of the impact of ZIF-8 structural regulation on drug delivery and proposes functionally oriented design strategies and methods. Modification strategies include: (i) doping other atoms on the surface of ZIF-8 or introducing targeting molecules such as folic acid (FA), hyaluronic acid (HA) and polyethylene glycol (PEG) to achieve targeted delivery, controlled release and versatile drug delivery; (ii) utilizing core–shell structures or cell membrane-coated ZIF-8 for biomimetic mineralization to promote on-demand drug delivery; (iii) combining cascades of multiple drug delivery mechanisms to optimize therapeutic effects; and (iv) developing composite ZIF-8 materials for smart drug delivery to enhance the responsiveness and precision of the delivery system (Scheme 1). In addition, this article also focuses on the customizable construction strategies and treatment mechanisms of ZIF-8-based tumor treatment platforms from single therapy to combination therapy and reviews the advantages and disadvantages of different synthesis methods and drug loading strategies of ZIF-8 (Tables 1 and 2). Finally, the potential clinical applications of ZIF-8-based drug delivery platforms and tumor treatment platforms are prospected, hoping to further promote their development in biological applications. In summary, we demonstrate that ZIF-8 is a highly functional and biocompatible nanomaterial for drug delivery and tumor therapy.

Scheme 1 Overview of ZIF-8 as a multifunctional platform for drug delivery and cancer therapy.

Table 2 Comparison of drug-loading strategies for ZIF-8-based systems: mechanisms, advantages, and disadvantages

Drug-loading strategy	Advantages	Disadvantages	Drug-loading mechanism
Adsorption method	Easy to operate, suitable for a variety of drugs, and no additional chemical modifications required	Low drug loading, limited drug release, and poor stability	Physical adsorption: drugs are adsorbed onto the ZIF-8 surface through electrostatic interactions, hydrogen bonding, or hydrophobic interactions
Co-precipitation method	High drug loading and simple operation, suitable for high release rate applications	Requires precise control of reaction conditions	Encapsulation: Drugs are encapsulated during the synthesis of the carrier, achieved by crystal growth
		Uneven drug distribution
		Some drugs may degrade or become inactive
Post-modification method	High drug loading and controlled release	Complex modification process	Covalent bonding: drugs are chemically conjugated or modified with the carrier (e.g., via amide or ester bonds)
	Adjustable hydrophilicity and release characteristics	Requires precise control of modifiers and conditions
	Various customization functions	High cost and process complexity

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2. Drug loading strategy of ZIF-8

The drug loading strategies of ZIF-8 can be mainly divided into adsorption methods, co-precipitation methods and post-modification methods. The adsorption method utilizes various interaction forces between drug molecules and synthesized ZIF-8, such as capillary force, electrostatic interaction, van der Waals force or coordination force, to combine the drug with ZIF-8. The co-precipitation method refers to adding drugs to the reaction solution during the synthesis of ZIF-8 crystals, so that the drugs and ZIF-8 crystals are formed simultaneously. The post-modification method introduces specific functional groups into the surface of ZIF-8 to adjust its surface properties so that it can selectively adsorb drug molecules. Different drug loading strategies have their own advantages and disadvantages, which are described in Table 2.

2.1. Adsorption method

In this strategy, the drug is typically present in solution or suspension, and ZIF-8 crystals are then brought into contact with the drug solution or suspension. Since ZIF-8 has a highly ordered pore structure and large surface area, drug molecules will be adsorbed onto the surface or inside the pores of ZIF-8 to form a drug-loaded complex. For example, Soltani et al. dissolved gentamicin (GEN) in a methanol solution, then added it to pre-synthesized ZIF-8 particles and soaked them for 5 days, so that GEN was adsorbed onto the surface or inside the pores of ZIF-8, and found that its drug-loading amount can reach 19%. After centrifugal washing and drying, the ZIF-8-coated GEN complex (ZIF-8@GEN) was obtained.⁶ The loading of GEN on ZIF-8 is mainly achieved through hydrogen bonding and electrostatic adsorption. Shearier et al. ball-milled the synthesized ZIF-8 particles, dispersed them into phosphate buffer, added hydroxyurea, and wrapped hydroxyurea on ZIF-8 using van der Waals forces. This study adopted a surface defect strategy to enhance the hydrophilicity of ZIF-8's outer surface without blocking its internal pore structure. In addition, the release of hydroxyurea and its toxicity to cells by ZIF-8 with and without external surface treatment were evaluated. The study found that 5 minutes of ball milling changed the hydrophobic and hydrophilic balance of ZIF-8, significantly improving cell activity without affecting its hydroxyurea loading and release capabilities.³³

In order to prepare efficient bactericidal materials, Tan et al. added zinc nitrate solution dropwise to the 2-MIM solution. After stirring for a moment, they added emodin methyl ether (Phy) solution. After one minute, the solution changed from milky white to yellow suspension, at which time Phy@ZIF-8 nanoparticles were formed. Silver nanoparticles (Ag NPs) and HA were then added, and the final Ag-Phy@ZIF-8@HA showed a bactericidal rate of 99.9%.³⁴ The release behaviors of Phy and Ag from Ag-Phy@ZIF-8@HA under different pH conditions, as well as its antimicrobial effects against Escherichia coli and Staphylococcus aureus, were further investigated (Fig. 1d). The results demonstrated that the material exhibited pH-responsive release and excellent antibacterial activity, with a minimum inhibitory concentration (MIC) significantly lower than that of conventional antibacterial agents. Wang et al. prepared ZIF-8 modified polyvinyl alcohol/chitosan (P/CSA) composite aerogels. First, P/CSA was soaked in a methanol solution containing Zn(NO₃)₂·6H₂O for 4 hours to allow as much Zn²⁺ to be adsorbed onto P/CSA as possible. Then, a methanol solution containing 2-MIM was added and magnetically stirred for 24 h. Through a series of adsorption experiments, it was found that the theoretical maximum adsorption capacity of ZIF-8@P/CSA for Congo red (CR) is as high as 1216.5 mg g⁻¹.³⁵

Fig. 1 (a) Schematic of an miR-34a-m@ZIF-8 composite system for synergetic gene/chemodynamic therapy.³⁶ Copyright 2021, American Chemical Society. (b) The synthesis route and in vivo pharmacodynamics of RVC@ZIF-8.³⁷ Copyright 2023, Wiley. (c) pH dependent release of AF-Cas9/sgRNA from CC-ZIFs.³⁸ Copyright 2018, American Chemical Society. (d) Phy and Ag release behaviors of Ag-Phy@ZIF-8@HA under different pH conditions, antimicrobial effects against Escherichia coli and Staphylococcus aureus, and MIC evaluation results.³⁴ Copyright 2022, Elsevier.

Zhao et al. proposed a ZIF-8-based miRNA delivery system (miR-34a-m@ZIF-8) for synergistic gene therapy and chemodynamic therapy to efficiently inhibit triple-negative breast cancer (Fig. 1a). ZIF-8 was loaded with miR-34a-m by co-adsorption, and its high specific surface area and pore volume achieved high loading capacity while protecting miRNA from RNase degradation. Both in vitro and in vivo experiments demonstrated that miR-34a-m@ZIF-8 exhibited stronger anti-tumor effects compared to free miR-34a-m, providing a new strategy for RNA delivery and synergistic gene/chemodynamic therapy.³⁶

Nguyen et al. loaded quercetin (QT) into ZIF-8 nanomaterials by adsorption. After the synthesis of ZIF-8 was completed, the QT solution was fully mixed and stirred with the ZIF-8 nanoparticles, so that QT was spontaneously adsorbed onto the surface and pores of ZIF-8 through physical and chemical interactions to form a QT@ZIF-8 complex.³⁹ This method utilizes the high specific surface area and porous structure of ZIF-8 to achieve efficient loading of QT (439 mg g⁻¹), while effectively controlling drug release through pH response characteristics, reducing QT release at pH 7.4, and reducing drug loss in the blood circulation. This loading method is simple to operate, has a high drug loading capacity, and provides good support for drug stability and targeted delivery.

In summary, the adsorption method is simple to operate, does not require additional chemical modification steps, and is suitable for various types of drugs. However, since adsorption is a surface phenomenon, drug release is usually limited by the adsorption force. Overall, this drug loading strategy is a simple and effective method, suitable for applications where the release rate is not strict.

2.2. Co-precipitation method

The co-precipitation method is a straightforward approach where the drug is first dispersed or dissolved in a solution containing Zn²⁺ or 2-MIM, and during the synthesis of ZIF-8, the drug is simultaneously encapsulated within the ZIF-8 crystals. This method leverages the self-assembly properties of metal ions and organic ligands during ZIF-8 synthesis to effectively trap the drug inside its porous structure.

For example, to prolong the action time of the local anesthetic ropivacaine (RVC) and reduce its toxicity, Wang et al. developed ZIF-8-encapsulated RVC sustained-release microspheres (RVC@ZIF-8). They pre-synthesized ZIF-8, dispersed it ultrasonically in n-hexane, and dissolved RVC in the solution as the oil phase. This oil phase was then emulsified into a Tween-80 aqueous solution under ultrasonic conditions. After stirring at room temperature for six hours to evaporate n-hexane, RVC@ZIF-8 microspheres were obtained. These microspheres demonstrated a high drug loading rate exceeding 30% and provided a stable sustained release for at least 96 hours in vitro.³⁷ The synthesis route and the in vivo pharmacodynamics of RVC@ZIF-8 are depicted in Fig. 1(b), which illustrates the preparation process and the pharmacokinetic profile of the microspheres in vivo.

Similarly, Zheng et al. utilized a coordination polymer strategy by mixing the anti-tumor drug doxorubicin (DOX) with a zinc nitrate solution, forming a coordination polymer through zinc–drug interactions. Upon the addition of dimethylimidazole, DOX was successfully encapsulated into ZIF-8 with a drug loading capacity ranging from 14% to 20%.⁴⁰ In another study, Alsaiari et al. encapsulated Cas9 and sgRNA by first mixing them at a 1 : 1 molar ratio in phosphate-buffered saline (PBS) and then adding a 2-MIM solution. By gradually adding a zinc nitrate aqueous solution under mechanical stirring, the mixture transitioned from a transparent to an opaque state, signifying successful encapsulation of Cas9 and sgRNA into ZIF-8 channels, achieving a drug loading rate of 17%.³⁸ The pH-dependent release of AF-Cas9/sgRNA from CC-ZIFs, as shown in Fig. 1(c), demonstrates the controlled release behaviors under different pH conditions, highlighting the potential for efficient delivery.

Drugs can also be encapsulated during ZIF-8 synthesis in a solid-phase system. For instance, ball milling of ZIF-8 precursors with drugs can yield ZIF-8-drug complexes. This method achieved a drug loading efficiency of 83.5% for sodium alginate, with 6.68% loading capacity.⁴¹ In a phosphate buffer with pH 8, 84% of the drug was released gradually over eight hours, demonstrating excellent sustained release properties. The primary advantage of the co-precipitation method lies in its simplicity, as it directly integrates drug encapsulation during ZIF-8 synthesis without requiring additional post-modification steps. However, challenges remain regarding the formation processes of ZIF-8 and the drugs, which can impact drug loading efficiency and release behavior. Careful control of the co-formation process is crucial to achieving effective drug encapsulation and controlled release.

For example, Wang et al. proposed a green co-precipitation method to immobilize glucose oxidase (GOx) and NiPd hollow nanoparticles onto ZIF-8, forming a multi-enzyme system. By mixing Zn(NO₃)₂, 2-methylimidazole, and PVP-stabilized NiPd nanoparticles, ZIF-8(NiPd) nanoflowers were synthesized. The addition of GOx further produced GOx@ZIF-8(NiPd), which retained the enzymatic activity of GOx and the peroxidase-like properties of NiPd.⁴² This system exhibited excellent tandem catalytic efficiency and enabled both colorimetric and electrochemical glucose detection with high stability and functionality, making it a versatile platform for applications in biosensors, biofuel cells, and catalysis. Liu et al. proposed a DNA walker nanosystem based on ZIF-8@DNAzyme for high-sensitivity and high-specificity intracellular miRNA imaging. ZIF-8 was self-assembled on the surface of a DNAzyme-based DNA walker by reacting the PVP-stabilized DNAzyme-based DNA walker with zinc ions and 2-MIM in methanol solution to generate ZIF-8 nanostructures coated with the DNA walker.⁴³ The coating of ZIF-8 not only protects the DNA walker from intracellular nuclease degradation, but also releases Zn²⁺ as a catalytic factor in the acidic environment of tumor cells, ensuring high-activity reaction and synchronous delivery.

In addition to these advances in drug and gene delivery systems, osteosarcoma (OS) is also an important area where ZIF-8-based nanocomposites have shown significant therapeutic potential. Osteosarcoma is a common and malignant bone tumor that has been shown to respond well to novel drug delivery strategies, especially those containing RNA therapeutics such as miRNA and siRNA. Recent studies have shown that signaling pathways associated with inflammation, especially the NF-κB pathway, play a crucial role in the occurrence and progression of osteosarcoma. MicroRNAs (miRNAs), especially miR-506, have been shown to play an important role in regulating osteosarcoma cell proliferation, migration, and invasion. Therefore, ZIF-8-based delivery systems are considered to be ideal carriers that can effectively deliver miRNAs (such as miR-506) to inhibit the progression of osteosarcoma.

For example, in the study of Hu et al. on osteosarcoma, the role of the NF-κB pathway in the regulation of miR-506 and its effect on cell proliferation were highlighted. The study found that overexpression of miR-506 significantly inhibited the growth, migration, and invasion of osteosarcoma cells. These results indicate that the ZIF-8-based delivery system can not only deliver miRNA targeting osteosarcoma progression, but also enhance the combined efficacy of gene therapy and traditional chemotherapy, thereby achieving better therapeutic effects.⁴⁴

In addition, ZIF-8 can also be combined with PTT to further improve the efficacy of cancer treatment. ZIF-8 nanoparticles can be used as carriers of photothermal agents, such as polydopamine (pDA), and exhibit excellent photothermal conversion efficiency under near-infrared (NIR) radiation. In the study conducted by Yin et al., MTX was encapsulated in ZIF-8 and then modified with pDA to enhance the photothermal response. Under NIR radiation, pDA/MTX@ZIF-8 nanoparticles not only showed effective drug release, but also produced significant ablation effects on tumor cells, showing great therapeutic prospects. This synergistic effect combines chemotherapy with photothermal therapy, providing a new direction for the treatment of osteosarcoma.⁴⁵

The advantage of the co-precipitation method is that it is simple to operate and can directly realize drug encapsulation during the synthesis of ZIF-8 without additional post-modification steps. However, this method may be affected by the formation process of the drug and ZIF-8 crystals, and the drug loading efficiency and release behavior of the drug may be limited. Therefore, the co-formation process of drugs and ZIF-8 crystals needs to be carefully controlled in practical applications to achieve effective encapsulation and controlled release of drugs.

2.3. Post-modification method

The post-modification method significantly enhances the properties of ZIF-8 crystals by introducing specific ligands or modifiers during the synthesis process. These ligands interact with the metal ions or coordination centers on the ZIF-8 crystal surface, forming a modified layer that alters its hydrophilicity, drug loading capacity, and release characteristics, thereby improving its performance in drug delivery, catalysis, and other applications. For instance, Chinnathambi et al. successfully modified ZIF-8 by aminating it to form ED-ZIF-8 and conjugating FA to the surface through an amide bond, creating the FA@ED-ZIF-8 complex. When mixed with docetaxel (DTX) in a 2 : 1 ratio, this system achieved a drug loading efficiency of 91.6%, which was significantly higher than the 85.4% efficiency of unmodified ZIF-8.⁴⁶ Similarly, Wang et al. used PEG-NH₂ as a capping agent to control the size of ZIF-8 nanoparticles and modify their surface with PEG. These modified nanoparticles, encapsulated with DOX using a one-pot method, formed DOX@ZIF-8/PEG systems that exhibited pH-responsive drug release properties and demonstrated significant cancer cell-killing efficacy.⁴⁷ Beyond these modifications, ZIF-8 has also been utilized for co-delivery of drugs and other bioactive molecules, such as RNA or DNA, which is particularly valuable in synergistic therapies for cancer treatment. For example, Nie et al. designed a MOF-coated MnO₂ nanosheet system that could co-load DOX and a survivin-inhibiting RNA-cleaving DNAzyme (DZ).⁴⁸ This system achieved excellent loading capacities for both agents, exhibited stability under physiological conditions, and degraded rapidly in tumor cells to release both drugs and genes. Furthermore, the released Mn²⁺ activated the DZ, enhancing RNA interference and maximizing the anti-tumor effect through a combination of chemotherapy and gene therapy. Similarly, Wang et al. synthesized silica-metal–organic framework hybrid nanoparticles (SMOF NPs) by integrating ZIF-8 with silica, enabling the encapsulation of hydrophilic payloads like drugs and nucleic acids.⁴⁹ These nanoparticles, functionalized with PEG or targeting ligands, demonstrated high loading rates, pH-responsive drug release, and significant potential for applications such as genome editing and targeted cancer therapies. In summary, post-modification transforms ZIF-8 into a versatile platform for co-delivery systems, enabling the integration of drugs with therapeutic molecules like RNA and DNA to create multifunctional treatments. The biomedical applications of ZIF-8-based nanocomposites, including the examples reported by Nie et al. and Wang et al., are summarized in Table 3, which highlights the potential of these advanced systems for synergistic therapies, where the combined delivery of drugs and genes enhances therapeutic efficacy, particularly in oncology.

Table 3 Biomedical applications of ZIF-8-based nanocomposites for combined delivery and RNA loading

Nanocomposites	Payloads	Applications	Ref.
Apt-PEG-siRNA@ZIF-8	siRNA	Treating prostate cancer	50
Apt/(siRNA + GEF)@ZIF-8	GEF	Treating non-small cell lung cancer	51
	siRNA
EVs@ZIF-8@siRNA	siRNA	Treating osteoporosis in the elderly	52
utZIF-SOD	SOD	Treating ulcerative colitis	53
ZIF-8@CL&Resv	CL Resv	Antibacterial and anticancer	54
PEG/ZIF-8@HF	HF	Treating melanoma	55
FA-BSA@MTX@Se@ZIF-8	MTX	Treating breast cancer	56
OMV-PD1@ZIF-8@miR-34a	miR-34a	Treating breast cancer	57
miR@ZIF-8	miR-5106	Accelerate vascularized bone regeneration	58
	miR-21
G3@ZIF-8	G(IIKK)I-NH	Treating colorectal cancer	59

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In summary, this drug loading strategy achieves functionalization of ZIF-8 crystals through surface modification and chemical coupling, significantly improves their drug loading capacity and controlled release properties, and enhances their use in biomedicine and other applications.

3. Integrating cascade reactions and smart mechanisms for multidrug delivery

The goal of drug delivery is to deliver the right dose of drugs to the right location at the right time to improve drug efficacy, reduce costs, and reduce adverse reactions. As a drug carrier, ZIF-8 has functions such as sustained release, targeting, microenvironmental response and protection, making it an ideal drug carrier. It is suitable for a variety of drugs, covering anti-tumor drugs, antibacterial drugs, proteins, enzymes, Ps, photothermal agents, imaging agents and other types. A variety of modification strategies have been used for ZIF-8 in drug delivery, which we will elaborate on from the following four perspectives: (i) by doping other metal atoms or introducing targeting molecules on the surface of ZIF-8 to achieve improved performance of drug delivery systems for targeted delivery, controlled release and versatility; (ii) by using core–shell structures or cell membrane-coated ZIF-8 for biomimetic mineralization to promote on-demand drug delivery; (iii) by combining cascade reactions of multiple drug delivery mechanisms to optimize therapeutic effects; and (iv) by developing composite ZIF-8 materials for smart drug delivery to enhance the responsiveness and accuracy of the delivery system. These modifications give ZIF-8 wider application potential, improve its applicability and effectiveness, and make it have richer application prospects in the field of drug delivery and biomedical engineering. The various modification strategies of ZIF-8 in drug delivery are summarized in Fig. 2, which provides a comprehensive overview of the different approaches.

Fig. 2 Overview of ZIF-8 modification strategies in the field of drug delivery.

Table 5 shows the advantages and disadvantages of different modification methods and applicable materials.

3.1. Doping with other metal atoms and surface functionalization

3.1.1. ZIF-8@other metal atoms. ZIF-8 doped with iron (Fe) or manganese (Mn): Balasamy et al. used an ultrasonication method to prepare nanocomposites of Fe/SBA-16 and ZIF-8 (Fe/S-16/ZIF-8). The material is a multifunctional platform combining biocompatible MOFs and magnetic nanocarriers for targeted delivery and imaging of the cancer drug cisplatin. The study investigated the drug release behavior of cisplatin from ZIF-8, Fe/S-16, and Fe/S-16/ZIF-8, as illustrated in Fig. 3(a). The results showed that the cisplatin release rate from Fe/SBA-16/ZIF-8 reached 75% within 72 hours, significantly higher than the 56% release rate of Fe/S-16 and the 7.5% release rate of ZIF-8 alone. This enhanced release profile highlights the potential of Fe/SBA-16/ZIF-8 as an efficient drug delivery system. Additionally, Fe/SBA-16/ZIF-8 exhibited a concentration-dependent inhibitory effect on MCF-7 cells, outperforming its effects on HeLa and HFF-1 cells. This suggests its selectivity and efficacy in targeting specific cancer cell types.

Fig. 3 (a) Cisplatin drug release by ZIF-8, Fe/S-16 and Fe/S-16/ZIF-8.⁶⁰ Copyright 2019, Royal Society of Chemistry. (b) In vivo NIR-II fluorescence imaging of a tumor-bearing mouse injected intratumorally with LDNPs@Fe/Mn-ZIF-8 solutions.⁶¹ Copyright 2022, American Chemical Society. (c) Cell viability measurements for the prepared samples, including pure CS/BC nanofibers and CS/BC-100%ZIF-8 and CS/BC-xAg@ZIF-8 nanocomposites.⁶² Copyright 2022, Elsevier (d) evaluation of the antibacterial properties of Au@ZIF-8 materials under laser irradiation.⁶³ Copyright 2023, Elsevier.

In summary, the paramagnetic Fe/SBA-16/ZIF-8 composite demonstrates considerable potential due to its therapeutic efficacy and promising applications in magnetically driven cancer therapy, antimicrobial and antibiotic treatments. Furthermore, it can be combined with biocompatible polymers, natural antioxidants, and macromolecular anticancer drugs for enhanced functionality.⁶⁰ In addition, Kumar et al. successfully synthesized a curcumin-immobilized imidazolate zeolite framework-8 (Cmim@ZIF-8) and used it as a fluorescent nanoprobe for metal ion sensing. They used this nanoprobe to sense metal ions of different valence states in aqueous media and observed that Cmim@ZIF-8 has good selectivity for Fe(II) metal ions. This discovery is an important breakthrough for the field of metal ion sensing, especially given its high selectivity for Fe(II). What's even more exciting is that inspired by these sensing results, they also applied this nanoprobe to biological imaging. By performing cell imaging in HepG2 cancer cells, they found that Cmim@ZIF-8 could even detect Fe(II) at the cellular level, indicating that this nanoprobe has great potential in the biomedical field. This research has far-reaching significance for the application of nanomaterials in sensing and bioimaging, opening up new possibilities for the future development of more precise and efficient biomedical imaging tools and sensors.⁶⁴ Due to its forbidden bandwidth and specific response to ultraviolet light, the photocatalytic anti-cancer application of ZIF-8 is still limited. Here, Li et al. developed a new nanocomposite LDNPs@Fe/Mn-ZIF-8 with dual-mode functionality for NIR-II imaging-guided photodynamic/chemical dynamic synergistic therapy. The material is composed of a Tm³⁺-doped NaErF₄:Tm core and an optimized Ce³⁺/Yb³⁺-doped NaGdF₄:Yb,Ce shell, which effectively reduces energy loss and enhances dual-mode emission. Through PVP coating and self-assembly of Fe/Mn-ZIF-8, the Fenton reaction inside the tumor is realized, triggering ˙OH generation and CDT. In addition, the degradation of Fe/Mn-ZIF-8 not only enhances the tumor-targeted fluorescence imaging function, but also consumes intratumoral glutathione by releasing metal ions, thereby enhancing the therapeutic effect. These properties make this nanocomposite a cutting-edge material with therapeutic and monitoring potential.⁶¹ As shown in Fig. 3(b), in vivo NIR-II fluorescence imaging of a tumor-bearing mouse injected intratumorally with LDNPs@Fe/Mn-ZIF-8 solutions demonstrates the material's excellent tumor-targeting and imaging capabilities, further validating its potential for integrated diagnosis and treatment. The addition of Fe or Mn improves the biocompatibility and bioactivity of ZIF-8 while enhancing its magnetism. This magnetic property enables directional drug delivery under the influence of an external magnetic field, making it suitable for magnetic field-assisted targeted drug release. By doping with Fe or Mn, ZIF-8 can not only serve as a drug delivery system but also function as a contrast agent for magnetic resonance imaging (MRI), achieving integrated disease diagnosis and treatment. This “theranostic” functionality represents a key development direction in modern medicine. Furthermore, Fig. 8(a) shows in vivo NIR-II fluorescence imaging of a tumor-bearing mouse injected intratumorally with LDNPs@Fe/Mn-ZIF-8 solution (500 μg mL⁻¹), demonstrating its excellent tumor-targeting ability and imaging function.

ZIF-8 doped with copper (Cu), silver (Ag) or gold (Au): in a recent study, Tanushree et al. explored the application of copper (Cu²⁺) doped ZIF-8 (Cu/ZIF-8) in drug delivery systems, especially in improving the stability of curcumin (Cur) and functional aspects. The doping of Cu optimized the surface charge of ZIF-8, enhanced its interaction with drug molecules, and significantly improved the drug loading (22%) and release efficiency (83%). Cu/ZIF-8 greatly improves the water-soluble stability of Cur through the complexation with Cu²⁺ and the metallization with Zn²⁺. In addition, the composite effect of Cu²⁺ and Zn²⁺ also promotes the generation of reactive oxygen species (ROS), strengthening Cur's resistance to bacteria and biofilms, making it more suitable for biomedical applications.⁶⁵ The doping of Ag or Au helps to improve the antibacterial properties of ZIF-8, making it antibacterial in drug delivery and suitable for applications such as local infection treatment. Another study conducted by Barjasteh et al. showed that Ag@ZIF-8 nanoparticles were synthesized by a green and environmentally friendly method and embedded in approximately 30 nm chitosan/bacterial cellulose (CS/BC) nanofibers. Transmission electron microscopy revealed the core–shell structure of the Ag@ZIF-8 nanostructure, in which the ZIF-8 core was covered by 5–20 nm silver nanoparticles. The introduction of Ag@ZIF-8 significantly enhanced the cell viability and antibacterial activity of CS/BC nanocomposites, providing an effective strategy for treating local infections.⁶²Fig. 3(c) shows the cell viability measurements for the prepared samples, including pure CS/BC nanofibers and CS/BC-100%ZIF-8 and CS/BC-xAg@ZIF-8 nanocomposites, which demonstrates enhanced cell viability with the incorporation of Ag@ZIF-8 nanoparticles. Ren et al. studied a new treatment strategy for bacterial biofilms, using an Au@ZIF-8 metal–organic framework as a peroxidase-like catalytic nanozyme, and using near-infrared laser to achieve photothermal treatment. Au@ZIF-8 exhibits excellent peroxidase-like activity and photothermal responsiveness, effectively destroying bacterial membranes and clearing up to 97% of Staphylococcus aureus (MRSA). In addition, it catalyzes the generation of free radicals from endogenous H₂O₂ and promotes the healing of infectious diabetic wounds, showing its great potential in the field of regenerative medicine.⁶³Fig. 3(d) shows the evaluation of the antibacterial properties of Au@ZIF-8 materials under laser irradiation, highlighting their effective antibacterial performance under photothermal treatment.

3.1.2. Surface functionalization of ZIF-8. In the field of drug delivery, chemical modifications targeting specific functions enable ZIF-8 to exhibit excellent application potential. Specifically, by introducing targeting groups on the surface of ZIF-8, recognition and binding to specific cells or tissues can be achieved, thereby promoting targeted delivery, effectively reducing side effects on normal tissues and enhancing therapeutic effects. In addition, by adjusting the surface chemical properties or structure of ZIF-8, drug release behavior can be precisely controlled, such as a controlled release mechanism in response to pH changes or temperature changes. ZIF-8 can also integrate multiple functions by introducing various functional groups, such as the combined application of targeted delivery and controlled release.

Folate binds strongly to folate receptors that are highly expressed on the surface of many tumor cells, making it an ideal targeting molecule. By modifying the surface of the nanoparticles with folic acid, the specific binding of the nanoparticles to tumor cells can be increased, along with their recognition and uptake. Bi et al. have prepared a novel folate functionalized (doxorubicin, DOX) DOX@ZIF-8 nanoparticle (DOX@ZIF-8-FA) as a targeted drug delivery system for liver cancer. This nano-delivery system exhibited a high drug loading capacity (15.7 wt%) with excellent sustained drug release performance and favorable pH response characteristics. Compared with free DOX and DOX@ZIF-8 nanoparticles, DOX@ZIF-8-FA nanoparticles showed a higher anticancer effect in HepG2 cells, indicating that folate-functionalized DOX@ZIF-8 nanoparticles are promising for targeted therapy of cancer cells.⁶⁶

To effectively target the delivery of chloroquine diphosphate (CQ) as an autophagy inhibitor, Shi et al. used a simple one-pot method to prepare ZIF-8 nanoparticles (CQ@ZIF-8 NPs) loaded with CQ and then used methoxy-polyethylene glycol-folic acid (FA-PEG) as a specific recognition agent for targeting cancer cells. The modified form is FA-PEG/CQ@ZIF-8. This drug delivery system provides new ideas for targeted cancer therapy by targeting specific receptors on the surface of cancer cells to more effectively enter and kill cancer cells.⁶⁷ Tian et al. developed a hybrid nanoparticle (POP@ZIF-8) based on a porphyrin-based organic polymer (POP) coated with a zeolite imidazole backbone ZIF-8, a novel cancer phototherapy strategy that uses special nanomaterials to deliver PS to tumor sites in a directed manner to improve the efficacy of phototherapy. This study provides a feasible and robust strategy for the development of stable and highly effective cancer phototherapeutic agents capable of simultaneously manipulating the structural properties and properties of targeted materials, opening up the possibility of promising non-invasive multimodal anti-cancer therapy.⁶⁸Fig. 4(a) shows the effects of different treatment groups on tumor and body weight changes in mice within 14 days, which further confirms the therapeutic potential of POP@ZIF-8 nanoparticles in cancer treatment.

Fig. 4 (a) Effects of different treatment groups on tumor and body weight changes in mice within 14 days.⁶⁸ Copyright 2023, Elsevier. (b) The standard curve for α-TOS solutions detected at 281 nm using a UV-vis spectrophotometer.⁶⁹ Copyright 2019, Elsevier. (c) In vivo antitumor therapy. Experimentation for the therapeutic model.⁶⁹ Copyright 2019, Elsevier.

HA, as an efficient targeting molecule, has been widely studied and used to enhance the tumor specificity of nanomedicine carriers. Shu et al. successfully loaded the anticancer drug DOX into ZIF-8 through a one-step method and coated it with dopamine polymer chelated iron ions (Fe³⁺) and HA to prepare a targeted and multifunctional ZIF-8 nanocarrier with imaging capabilities. This carrier can specifically release drugs under acidic conditions and shows significant therapeutic effects on prostate cancer PC-3 cells. At the same time, their magnetic properties allow them to be used as magnetic resonance imaging (MRI) contrast agents.⁷⁰ Furthermore, Sun et al. used a similar method to encapsulate the hydrophobic drug D-α-tocopherol (α-TOS) in ZIF-8 and surface-modified it with HA to form the HA/α-TOS@ZIF-8 nanoplatform. This design takes advantage of the CD44-targeting properties of HA to enhance drug accumulation at the tumor site and extend blood circulation time through the CD44-mediated pathway. In the tumor microenvironment, the HA shell can be broken down by hyaluronidase, leading to the breakdown of ZIF-8 and the release of drug-loaded α-TOS, thereby achieving tumor-specific and on-demand drug release.⁶⁹Fig. 4(b) presents the standard curve for α-TOS solutions detected at 281 nm using a UV-vis spectrophotometer, and Fig. 4(c) shows the in vivo antitumor therapy experimentation for the therapeutic model.

Among drug delivery systems, ZIF-8 is notable for its excellent pH-responsive release properties. This material is unstable under acidic conditions, allowing it to effectively release drugs in the acidic environment of tumors. This property makes ZIF-8 ideal for regulating drug release under specific physiological conditions. In addition to pH sensitivity, the drug release of ZIF-8 can also be precisely controlled by external stimuli, such as temperature, light, and magnetic fields, which increases the flexibility and application scope of the drug delivery system. In further applications in the field of nanomedicine, He et al. developed hybrid nanocomposites of C-dots and ZIF-8. They proposed a simple two-step synthesis method to obtain C-dots@ZIF-8 nanoparticles with green fluorescence and microporous properties. This new material can not only be used for fluorescence imaging of cancer cells, but also achieve pH responsiveness and drug release. This technology provides an important material basis for the construction of multifunctional biomedical platforms and also provides methodological support for the development of other fluorescent nanostructured hybrid materials.⁷¹ Pandey et al. used a lenalidomide–HA conjugate for loading a titanium nitrile complex into a lactoferrin (Lf) matrix and encapsulating 5-fluorouracil (5-FU) within ZIF-8. The surface modification of the ZIF-8 particles enabled the formation of this multifunctional nanocomposite, which demonstrates sustained drug release in simulated body fluids, strong cytotoxicity to cancer cells, and the ability to trigger oxidative stress responses in cells, highlighting its potential for brain tumor treatment.⁷² Furthermore, the UCNP/TiO₂/Cur@ZIF-8 nanocomposite created by Wen et al. combines pH and near-infrared light responsiveness, utilizing upconversion nanoparticles (UCNPs) and titanium dioxide nanoparticles (TiO₂ NPs) as well as the chemotherapy drug Cur interaction to enhance therapeutic effects through photosensitivity phenomena and energy upconversion.⁷³ In addition, several other applications of ZIF-8 complexes are also shown in Table 4, including targeted delivery to cancer cells, controlled drug release, and responsiveness to external stimuli such as pH.

Table 4 Application of ZIF-8 and its complexes in controlled release and drug stimulation response

Stimulus response type	Nanocomposites	Loaded drug	The release amount	Application	Ref.
pH	ZIF-8	5-FU	1 h-45%, 12 h-85%	Heal colorectal, breast, head and neck cancers	74
	ZIF-8@GA@Fe@5-FU	5-FU	12 h-54%	Head and neck cancers	75
	ZIF-8@GA@Fe@5-FU@Gox		12 h-82%
	ZIF-8@GA@Fe@5-FU@Au		12 h-69%	Breast cancer cell MDA-MB-231 treatment
	ZIF-8@LEVO@HA-PEI	LEVO	0.65 mg cm^−1	Inhibited bacterial adhesion and biofilm formation	76
	CCMZIF MN	CCM	40.5%	Skin disorders	77
	BA@ZIF-8-PDA-PEG	BA	10 h-57%	Lung cancer cell A549 treatment	78
	NOR-Fe3O4@ZIF-8	NOR	84 h-97%	Inhibit the actions of microorganisms	79
	LND-HA@ZIF-8@Lf-TC	Lf + 5-FU	48 h-92.59	Treat glioblastoma	72
	ZDOS	DOX	48 h-75%	HeLa cells and MCF-7 cell treatment	80
Targeting	UCNP@ZIF-8/FA	5-FU	24 h-82%	HeLa cell treatment	81
	PEG-FA/PEGCC@ZIF-8	PEGCG	10–90%	Cervical cancer therapy	82
	CCM@ZIF-8/HA	CCM	4 days >80%	Cervical cancer therapy	83
	HA/α-TOS@ZIF-8	α-TOS	25 h-74%	HeLa cell treatment	69
Multi-responsive	ZIF-8@GA	GOX + DHA	192 h-89.2%	Treat osteosarcoma	45
	ZIF-8/DOX-HA@MIP	DOX	25 h-80%	Treat prostate cancer	84
	HA/SA/P-ZIF	PHMB	72 h-80%	Infected burn wound healing	85
	UCNP/TiO2/Cur@ZIF-8	Cur	24 h-85%	Inhibit the tumor growth	86

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3.2. Biomimetic mineralization and core–shell structure

Biological macromolecules, such as antibodies, have become key tools in modern disease treatment and scientific research. However, these biopharmaceuticals often face challenges such as poor stability and easy aggregation or degradation. In this context, improving the stability of functional biomolecules has become a major challenge in biotechnology. The development of simple and effective methods to stabilize biomolecules will significantly improve their applications in pharmaceuticals, chemical processing, and biological storage. Among them, biomimetic mineralization technology has become an effective strategy by imitating the biomineralization process and depositing inorganic crystals on organic or inorganic templates. By using organic templates or surface-modified biological macromolecules as crystal seeds, biomimetic mineralization of ZIF-8 can achieve precise control of the morphology and structure of the seed crystals under controlled deposition conditions.

Falcaro et al. used a biomimetic mineralization process to encapsulate biomolecules in MOFs, effectively inducing the MOFs to form a porous crystalline shell under physiological conditions and providing unprecedented protection for biomolecules that are usually easily degraded. For example, enzymes encapsulated in MOF shells remain biologically active even at high temperatures and upon treatment with organic solvents.⁸⁷ Shi et al. introduced an innovative in-situ biomimetic mineralization strategy applied to ZIF nanocrystals to construct a drug release system with good cytocompatibility, improved stability, and pH responsiveness. This process involves encapsulating lysozyme (Lys) on the ZIF-8 surface and promoting the formation of bone-like hydroxyapatite (HAp) through biomimetic mineralization, forming a complex with a hollow Lys/ZIF-8 core and HAp shell (Fig. 5(c)). In vitro studies show that these complexes have high drug loading efficiency (56.5%), smart pH-responsive drug release, good cell compatibility, and stability under physiological conditions. Additionally, Fig. 5(d) demonstrates the in vitro anticancer activity of HeLa cells after incubation with different concentrations and times of free DOX and DOX-HAp@Lys/ZIF-8, as measured by MTT assay. These results provide opportunities for the application of MOF-based complexes in the biomedical field and propose a new design path.⁸⁸

Fig. 5 (a) Schematic of the development of DSF@Z-NPs and selective release of DOX from DSF@Z-NPs into cancer cells and (b) controlled DOX release from DSF@Z-NPs in response to acidic pH.⁸⁹ Copyright 2021, American Chemical Society. (c) Schematic illustration of the synthesis process of HAp@Lys/ZIF-8 nanoparticles for pH-triggered drug delivery and (d) in vitro anticancer activity of HeLa cells after incubation with different concentrations and times of free DOX and DOX-HAp@Lys/ZIF-8 by MTT assay.⁸⁸ Copyright 2020, American Chemical Society. (e) Antitumor activity of the CYP450 reactor.⁹⁰ Copyright 2023, Wiley.

The hollow core of ZIF-8 is formed by zinc ions and 2-methylimidazole through a coordination reaction and has a porous structure. This hollow core can accommodate and embed drug molecules to form a stable core region. When a drug molecule is embedded in the porous structure of ZIF-8, the drug typically interacts with the framework of ZIF-8, possibly binding to the ligand in the framework through electrostatic interactions, hydrogen bonding, or other interaction forces. This interaction helps to maintain the stability of the drug and allows for controlled release of the drug by modulating the properties of ZIF-8. Overall, the core–shell structure composed of ZIF-8 and the drug has the dual advantage of providing highly controllable carrier properties by utilizing the porous structure of ZIF-8, as well as protection and controlled release of the drug through drug embedding, which makes it potentially promising for application in the field of nanodrug delivery.

Zheng et al. successfully synthesized multi-level core–shell ZnO-DOX@ZIF-8 nanoparticles, which include a mesoporous ZnO core and a microporous ZIF-8 shell, where the ZnO core is responsible for loading the anti-cancer drug DOX, acting as a drug reservoir, while the ZIF-8 shell prevents premature release of the drug in a physiological environment. These nanoparticles can release more than 80% of the drug under acidic conditions of pH 5.5, showing excellent pH responsiveness.⁹¹ Chen et al. constructed a drug delivery system by combining filipin (SF) with ZIF-8. They first assembled SF into nanoparticles (SF-NPs) and then loaded DOX to form DSF-NPs. These nanoparticles further serve as templates to promote the nucleation of ZIF-8, forming DSF@Z-NPs with a core–shell structure. This structure promotes the dissolution of the ZIF-8 shell in the acidic intratumoral intracellular environment, thereby selectively releasing DOX. In vivo experiments show that DSF@Z-NPs can effectively inhibit tumor growth and improve the survival rate, verifying its application potential. Chen et al. constructed a drug delivery system by combining filipin (SF) with ZIF-8. They first assembled SF into nanoparticles (SF-NPs) and then loaded DOX to form DSF-NPs. These nanoparticles further serve as templates to promote the nucleation of ZIF-8, forming DSF@Z-NPs with a core–shell structure. This structure promotes the dissolution of the ZIF-8 shell in the acidic intratumoral intracellular environment, thereby selectively releasing DOX into cancer cells (Fig. 5(a)). Additionally, the controlled release of DOX from DSF@Z-NPs in response to acidic pH is demonstrated (Fig. 5(b)), highlighting the pH-sensitive nature of the drug delivery system. In vivo experiments show that DSF@Z-NPs can effectively inhibit tumor growth and improve the survival rate, verifying its application potential in cancer treatment.⁸⁹ Wang et al. used ZIF-8 to co-encapsulate enzymes and prodrugs in the same particle to form a core–shell structure reactor, including a ZIF-8 core and a Zn-DTIC framework shell. This structure integrates the anticancer drug dacarbazine (DTIC) with cytochrome P450 (CYP450), ensuring the high stability of the reactor in a physiological environment and allowing simultaneous delivery of enzymes and prodrugs within tumor cells. This system exhibits NADPH-sensitive in situ drug activation specificity in tumor cells and significantly improves prodrug conversion efficiency. Taking advantage of the tumor-targeting properties of hyaluronic acid, this core–shell enzyme reactor demonstrated excellent tumor inhibition in mouse melanoma models (Fig. 5(e)), providing an innovative strategy for high efficiency, selectivity, and safety in biocatalysis.⁹⁰ These studies demonstrate the great potential of nanodrug delivery systems based on ZIF-8 biomimetic mineralization and core–shell structure in achieving drug stability, controlled release, and improved efficacy, providing new opportunities for future cancer treatment and other drug delivery applications.

3.3. Integrating cascade reactions and smart mechanisms for multidrug delivery

ZIF-8-based drug delivery systems provide a highly controllable and complex method to achieve multi-drug delivery and precise drug release under specific conditions through cascade reactions and intelligent response mechanisms. These systems combine mechanisms such as pH sensitivity, light-triggered release, and temperature response to adapt to the acidic tumor microenvironment or specific external stimuli, thereby achieving the orderly encapsulation and release of multiple drugs (such as chemotherapy drugs and immunotherapeutics) and exerting synergistic therapeutic effects to a greater extent. For example, Rashmi et al. achieved pH-responsive release of Cur through a FA-modified ZIF-8 carrier, significantly improving tumor cell toxicity;⁹² Zhang et al. used ZIF-8 to encapsulate DOX and a P-glycoprotein inhibitor (VER), which achieved targeted delivery through PEG-FA modification, successfully overcoming the problem of multidrug resistance in cancer treatment.⁹³

In another research, Song et al. combined DOX with HA to construct a multifunctional ZIF-8 system, which showed good prostate cancer targeting effects;⁹⁴ Yang et al. used an environmentally friendly one-pot method to load DOX on ZIF-8, combined with WP6 and FA targeting functions, which significantly enhances the water dispersibility and anti-cancer efficacy of nanoparticles.⁹⁵ These studies prove that ZIF-8-based intelligent response systems can effectively achieve precise drug delivery and targeted therapy. However, ZIF-8 still has certain limitations in drug delivery, especially its low affinity for non-charged drugs and lack of surface functional groups. To address this problem, Yan et al. developed the “prodrug-ZIF-8” platform, which used the pH-sensitive prodrug CAD to improve the drug loading capacity of ZIF-8 and combined it with folic acid to achieve tumor-targeted delivery, effectively reducing cardiotoxicity and enhancing the therapeutic effect.⁹⁶ The efficacy of this platform was demonstrated through a series of in vivo experiments, as illustrated in Fig. 6. The results showed a significant reduction in tumor volume (Fig. 6a) and tumor weight (Fig. 6c) in mice treated with CAD@ZIF-8-FA NPs compared to control groups. Additionally, the tumors from different treatment groups were visually compared (Fig. 6b), further confirming the effectiveness of the treatment. Bodyweight changes during the treatment (Fig. 6d) indicated that the therapy was well-tolerated by the mice. In vivo fluorescence imaging (Fig. 6e) revealed the accumulation of CAD@ZIF-8-FA NPs in tumors over time, highlighting the targeted delivery capability of the platform. Ex vivo bioluminescence imaging of different organs (Fig. 6f) and H&E staining (Fig. 6g) provided further evidence of reduced systemic toxicity and enhanced therapeutic efficacy of the treatment. The fabrication process of CAD@ZIF-8-FA NPs as a versatile nanovehicle for cancer treatment via i.v. injection is depicted in Fig. 6h. In addition, Su et al. constructed a highly efficient pH-responsive joint drug delivery system by encapsulating Cur and indocyanine green (ICG) in ZIF-8, showing excellent drug loading efficiency and thermal performance, which provides a solution to the acidic environment of tumors. It provides new ideas for drug release challenges.⁹⁷ Silva et al. further designed a thermally responsive nanomaterial (ZIF-8, EuxTby@AuNP), which combined lanthanide ion temperature monitoring and AuNP heating to achieve drug release and multifunctional treatment through visible light stimulation, expanding the application prospects of intelligent drug delivery systems.⁹⁸

Fig. 6 (a) Change in tumor volume during treatment. (b) Photo of tumors from different groups. (c) Tumor weight change during therapy. (d) Bodyweight changes during the treatment. (e) In vivo fluorescence imaging of MDA-MB-231 bearing mice at 1, 12, 24, 48, and 72 h after the injection of free DOX and CAD@ZIF-8-FA NPs. (f) Ex vivo bioluminescence imaging of different organs. (g) H&E staining of different organs. (h) Fabrication of CAD@ZIF-8-FA NPs as a versatile nanovehicle for cancer treatment by i.v. injection.⁹⁶ Copyright 2020, American Chemical Society.

In addition, antibody–nanoparticle conjugation technology provides strong support for precise drug delivery and successfully solves the key challenges of directional attachment and activity retention of antibodies. For example, the ZIF-8 film coating technology developed by Zhang et al. uses Zn²⁺ to form specific coordination bonds with histidine in the Fc region of the antibody to achieve the embedding and directional connection of the antibody, ensuring that the Fab region is exposed to the biological target, thus significantly enhancing cell targeting ability. Compared with traditional chemical connection methods, this technology is simple and efficient, with cell targeting efficiency increased by about three times. It is suitable for different types of nanomaterials and shows broad application potential in fields such as drug delivery, phototherapy and bioimaging.⁹⁹

On this basis, Jiang et al. further developed a tumor microenvironment-responsive intelligent nanosystem, KN046@19F-ZIF-8, for integrated diagnosis and treatment, which is used for immune checkpoint combined therapy and 19F-MRI real-time imaging.¹⁰⁰ KN046 is a PD-L1/CTLA-4 bispecific single domain antibody-Fc fusion protein that can simultaneously block the PD-L1 and CTLA-4 signaling pathways, thereby significantly enhancing the anti-tumor immune response. By encapsulating KN046 in fluorine-doped ZIF-8 nanoshells, ZIF-8 is rapidly decomposed in the weakly acidic and high glutathione (GSH) environment of the tumor, achieving controlled release of KN046 and activating the 19F-MRI probe at the same time realizing drug release monitoring and real-time imaging. Research results show that KN046@19F-ZIF-8 achieves precise release of KN046 at the tumor site, effectively reduces the toxic side effects of normal tissues, and significantly enhances the effect of immunotherapy through a dual immune checkpoint blocking strategy. In addition, combined with 68Ga-NOTA-GZP PET/CT technology, non-invasive real-time monitoring of immune activation status within tumors has been successfully achieved, providing imaging support for immunotherapy. This intelligent system improves the efficacy and bioavailability of immunotherapy by integrating precise drug release, immunotherapy and real-time diagnostic imaging and is expected to delay or overcome resistance to monoclonal antibody therapy.

In summary, the ZIF-8-based drug delivery system not only provides innovative solutions for multi-mechanism response and multi-drug synergistic release, but also overcomes drug delivery challenges through intelligent mechanisms and directional coupling technology. Although there are still complexities in material confinement and release coordination, with the deepening and optimization of research, these systems are expected to be more widely used in clinical applications and provide strong technical support for precision treatment and integration of diagnosis and treatment.

4. ZIF-8 in cancer therapy: challenges and strategies for enhanced efficacy

The various ways of anti-tumor treatment include chemical drug therapy, photothermal therapy, photodynamic therapy, chemodynamic therapy and sonodynamic therapy, and in order to improve the efficacy, combined treatment strategies are often adopted. In these therapeutic methods, ZIF-8 serves as a carrier that, through its unique pH-responsive properties, can effectively load the corresponding drugs or other functional materials, such as materials with light and thermal responses, to achieve the desired treatment effect. In acidic environments, ZIF-8 has a unique ability to disintegrate, which is not possessed by many other metal–organic frameworks such as UiOs and MILs. This disintegration characteristic is mainly due to the protonation of the organic ligand of ZIF-8 in an acidic environment, which leads to the dissociation of the coordination bond between the metal ion cluster and the imidazole ligand, destroying the framework structure. This mechanism allows ZIF-8 to disintegrate after reaching the weakly acidic environment of the tumor, thereby achieving slow release of the drug and enhancing the accuracy and effect of treatment.

In addition, the application of ZIF-8 in the field of diagnosis is also significant. Through specific surface modification, ZIF-8 can achieve responsive release at the tumor site, increasing its relative concentration in tumor tissue, thereby improving the image contrast with normal tissue. This characteristic allows ZIF-8 to not only serve as a carrier for therapeutic agents, but also serve as a multifunctional diagnostic and treatment platform for tumors, enabling real-time monitoring of treatment effects. These characteristics indicate that ZIF-8 is not only an effective drug delivery system, but also a potential diagnostic tool, providing a new way to integrate treatment and diagnosis for modern medicine.

4.1 Chemodynamic therapy: mechanism and ZIF-8 optimization

CDT is an advanced anti-tumor treatment strategy. Its core mechanism is to generate ROS through chemical reactions and induce oxidative stress in tumor cells to achieve therapeutic purposes. In a specific TME, that is, under weakly acidic, high H₂O₂ and low oxygen conditions, CDT converts H₂O₂ into highly oxidative hydroxyl radicals (˙OH) by triggering the Fenton reaction. These strongly oxidized ˙OH free radicals accumulate in the TME, causing an increase in intracellular oxidation levels, ultimately leading to DNA damage, protein inactivation, and lipid oxidation, thereby inducing tumor cell apoptosis. In this process, ZIF-8, as a metal–organic framework, is widely used to effectively deliver the H₂O₂ and Fenton reaction catalysts required for CDT to designated tumor cells.¹⁰¹ Although traditional CDT has some limitations, such as the amount of H₂O₂ may not be enough to produce sufficient ˙OH, researchers have improved the therapeutic effect by improving the catalyst to optimize the Fenton reaction in the TME. In addition, many studies have combined ZIF-8 with other functional materials to achieve multimodal treatment effects. For example, by integrating nanomaterials with photothermal therapeutic effects into ZIF-8, it is endowed with the ability to be used for both CDT and PTT. This integrated strategy optimizes the treatment effect at multiple levels, not only enhancing the Fenton reaction by improving the catalyst, but also introducing the concept of multimodal treatment, which greatly enriches the application prospects of CDT.

Next, we will further explore three optimization strategies for ZIF-8 in CDT: one is to improve the catalyst to optimize the Fenton reaction to improve the efficacy of CDT; the other is a multi-modal treatment strategy based on CDT; the third is to use innovative cell death pathways to enhance the efficacy of CDT. The implementation of these strategies not only deepens our understanding of the CDT mechanism, but also helps to develop more effective anti-tumor treatments (Fig. 7).

Fig. 7 ZIF-8-based CDT mechanism.

4.1.1. Modification of catalysts to optimize the Fenton reaction for improved efficacy. Catalysts were modified to optimize the Fenton reaction for improved efficacy, addressing the unique characteristics of the TME. Cancer cells often exhibit high metabolic activity, leading to elevated levels of H₂O₂, weak acidity, and GSH overexpression in the TME, which are key factors in tumor progression. CDT leverages these conditions by using Fenton reagents to catalyze the conversion of H₂O₂ into highly toxic ˙OH, thereby inducing oxidative damage to tumor cells. However, the limited endogenous H₂O₂ levels in certain cancers, such as glioblastoma and pancreatic cancer, can hinder the effectiveness of this therapy. To overcome this limitation, researchers have developed strategies to increase H₂O₂ concentration and optimize Fenton reactions. Li et al. successfully developed Fe/Mn bimetal-doped ZIF-8 (Fe/Mn-ZIF-8), which covers the surface of LDNPs to form LDNPs@Fe/Mn-ZIF-8. This composite achieves a synergistic effect of CDT and PDT guided by tumor imaging (NIR-II imaging). The responsive degradation of Fe/Mn-ZIF-8 in the H₂O₂, H⁺, and GSH-rich environment of the TME enables the release of Fe²⁺/Mn²⁺ ions, promoting the production of ˙OH through CDT. Moreover, high-valent metal ions generated through Fenton and Fenton-type reactions deplete GSH in cancer cells, protecting ROS from scavenging and enhancing the therapeutic effect. The mechanism can be summarized as follows: (i) Catalyst + NIR + O₂ → Catalyst(e⁻) + ˙O₂⁻; (ii) Catalyst + GSH/H⁺ → Fe²⁺ + Mn²⁺ + GSSH; (iii) Fe²⁺ + Mn²⁺ + H₂O₂ → ˙OH + Mn³⁺/Mn⁴⁺ + Fe³⁺; and (iv) Mn³⁺/Mn⁴⁺ + Fe³⁺ + GSH → Fe²⁺ + Mn²⁺ + GSSH.⁶¹ In addition, the CaO₂/DOX@Cu/ZIF-8@HA (CDZH) structure developed by Cui et al. can significantly increase the production of oxygen and ROS under different pH conditions, especially in acidic environments, thus effectively producing the oxidative stress required for CDT. This structure supplies H₂O₂ through Cu-Fenton type reaction and combines with highly active hydroxyl radicals, exhibiting excellent chemical/chemical dynamic synergistic therapeutic capabilities. In this process, the reaction mechanism of CaO₂ includes: CaO₂ + H₂O₂ → O₂ + Ca(OH)₂ and CaO₂ + 2H₂O → H₂O₂ + Ca(OH)₂.¹⁰² Finally, Li et al. synthesized GOD@Cu-ZIF-8 through a one-pot biomimetic mineralization method. When applied to tumor sites, the protonation of 2-methylimidazole can trigger the decomposition of GOD@Cu-ZIF-8, releasing a large amount of Cu²⁺ and GOD. This reaction depletes intracellular GSH by reducing Cu²⁺, while GOD-catalyzed oxidation of intratumoral glucose significantly increases H₂O₂ levels, allowing Cu to convert it into highly toxic ˙OH, thereby enabling efficient cancer therapy (Fig. 8b). The content of GSH in 4T1 cells treated with PBS, ZIF-8, Cu-ZIF-8, and GOD@Cu-ZIF-8 for 6 hours was measured and is shown in the figure. Additionally, LSCM images (Fig. 8c) revealed the mass of ˙OH in 4T1 cells treated with different formulations, including GOD@Cu-ZIF-8, GOD@ZIF-8, Cu-ZIF-8, ZIF-8, and PBS for 12 hours. The quantitative fluorescence intensity of APF and DCF in 4T1 cells is shown in Fig. 8d, providing insight into the oxidative stress induced by the treatments. Moreover, LSCM images of total ROS in 4T1 cells (Fig. 8e) further illustrate the effect of these formulations on ROS production after 12-hour incubation. Cell proliferation, analyzed using CCK-8, is presented in Fig. 8f, showing the therapeutic potential of GOD@Cu-ZIF-8. LSCM images of live/dead analysis (Fig. 8g) and FCM analysis of cellular apoptosis (Fig. 8h) demonstrate the cell death induced by GOD@Cu-ZIF-8 treatment after 12 hours. Altogether, these strategies optimize CDT by addressing the metabolic and biochemical characteristics of tumors, providing precise and effective methods for cancer treatment. By targeting specific features of the TME, these advancements hold promise for improving therapeutic outcomes across various cancer types.¹⁰³ Altogether, these strategies optimize CDT by addressing the metabolic and biochemical characteristics of tumors and targeting specific features of the TME, providing precise and effective methods that hold promise for improving therapeutic outcomes across various cancer types.

Fig. 8 (a) In vitro NIR-II fluorescence imaging of LDNPs@Fe/Mn-ZIF-8 solutions with different concentrations and in vivo NIR-II fluorescence imaging of a tumor-bearing mouse injected intratumorally with LDNPs@Fe/Mn-ZIF-8 solutions (500 μg mL⁻¹).⁶¹ Copyright 2022, American Chemical Society. (b) Content of GSH in 4T1 cells treated with PBS, ZIF-8, Cu-ZIF-8, and GOD@Cu-ZIF-8 for 6 h. (c) LSCM images of mass of ˙OH in 4T1 cells treated with GOD@Cu-ZIF-8, GOD@ZIF-8, Cu-ZIF-8, ZIF-8, and PBS for 12 h. (d) Quantitative fluorescence intensity of APF and DCF in 4T1 cells. (e) LSCM images of total ROS in 4T1 cells treated with GOD@Cu-ZIF-8, GOD@ZIF-8, Cu-ZIF-8, ZIF-8, and PBS for 12 h. (f) Cell proliferation analyzed by CCK-8. (g) LSCM images of live/dead analysis and (h) FCM analysis of cellular apoptosis after incubation with GOD@Cu-ZIF-8, GOD@ZIF-8, Cu-ZIF-8, ZIF-8, and PBS for 12 h.¹⁰³ Copyright 2023, American Chemical Society.

4.1.2. CDT-based multimodal treatment strategy. In cancer treatment, the TME plays a key role in promoting tumor progression and therapeutic resistance. The main features of the TME, such as hypoxia, weak acidity, excess GSH, and dysregulated glucose metabolism, pose significant challenges to traditional therapies. The development of nanotherapeutic systems that integrate multiple therapeutic modalities into a single platform has emerged as a promising strategy to address these complexities. By combining complementary mechanisms, these systems improve therapeutic efficacy and specificity, especially for cancers such as breast cancer, hepatocellular carcinoma, and colorectal cancer that exhibit highly variable and adaptive microenvironments.

Chu et al. developed an innovative nanostructure, iron-doped ZIF-8 (FZID), designed to combine the chemotherapeutic drug DOX with the photothermal conversion agent ICG. This biodegradable nanosystem integrates CDT, PTT, and traditional chemotherapy, thereby improving the therapeutic efficacy. The iron ions in FZID triggered an efficient Fenton reaction, generating ˙OH to induce oxidative stress, while PTT further damaged the cancer cell membrane and improved the effectiveness of CDT. Under acidic conditions (pH 5.0), the release rates of DOX and ICG reached 81.1% and 80.2%, respectively, and the photothermal conversion efficiency was 35.9%. These synergistic effects significantly increased the mortality of cancer cells to 93.7%, demonstrating the potential of FZID in treating cancers with hypoxic and acidic microenvironments.¹⁰⁴

In addition, the CaO₂ system developed by Liang et al. also showed great potential to promote CDT by providing sufficient H₂O₂ and oxygen in the tumor microenvironment. The CaO₂@DOX@Cu/ZIF-8 system synthesized by them rapidly decomposed in the acidic environment of tumors, releasing DOX, CaO₂, and Cu²⁺. These Cu²⁺ ions not only catalyze the generation of H₂O₂, but also generate highly toxic ˙OH through the Fenton reaction. At the same time, the generated oxygen improves the hypoxic environment inside the tumor and enhances the sensitivity of tumor cells to the chemotherapy drug DOX, thus improving the efficacy of chemotherapy. In vitro experimental results show that the apoptosis rate of this nanostructure in tumor cells reaches 80.6%, effectively demonstrating the combined advantages of CDT and chemotherapy.¹⁰⁵

Another innovative composite material, GOx@Pd@ZIF-8, integrated GOx and palladium nanozyme (Pd) within the ZIF-8 framework to disrupt glucose metabolism in cancer cells. GOx blocked glucose metabolism, while Pd catalyzed the production of ROS, thereby enhancing oxidative stress in tumor cells. In vivo and in vitro experiments confirmed its efficacy in inhibiting tumor proliferation, migration, and invasion with minimal side effects on normal tissues. RNA sequencing revealed its molecular mechanism, providing a stable and effective strategy for multimodal anticancer therapy.¹⁰⁶

Li et al. designed a degradable nanocatalyst Cu/ZIF-8@DSF-GOD@MnO₂ (CZ-DG-M) to enhance the combined effect of ammonium disulfide (DSF) chemotherapy and CDT. By incorporating glucose oxidase (GOD) and coating the system with manganese dioxide (MnO₂), the catalyst efficiently consumes GSH and produces oxygen in the TME.¹⁰⁷ This mechanism is particularly beneficial for cancers with high GSH levels, which often exhibit resistance to chemotherapy. The MnO₂ shell enhances GOD-catalyzed production of H₂O₂, while the released Cu²⁺ ions chelate with DSF to form the highly toxic CuET product. In vivo and in vitro experiments showed that the therapy significantly inhibited tumor growth while enabling precise tumor localization and treatment monitoring via T1 MRI.

Overall, the CDT-based multimodal treatment strategy effectively integrates multiple therapeutic modalities to address the complexity of the TME, including hypoxia, GSH overexpression, and dysregulated glucose metabolism. These advances provide highly targeted and effective cancer treatments, paving the way for a broader range of applications in various cancer types.

4.1.3. Based on other cell death pathways created by CDT to enhance efficacy. In the field of CDT research, exploring new cell death pathways to enhance therapeutic efficacy has become an important frontier direction in cancer treatment. In particular, activating the regulatory cell death mechanism, ferroptosis, has shown great potential in the clinical treatment of complex tumors. Although ferroptosis inducers may be limited by a variety of endogenous factors when used alone, this limitation can be effectively overcome by adopting synergistic treatment strategies to achieve better therapeutic effects. In response to this mechanism, Li's research team successfully developed an iron-containing metal organic framework (Fe/ZIF-8), which is equipped with GOx and L-arginine (L-arg) and loaded with the chemotherapy drug DOX. Targeted delivery is achieved through FA modification. This composite nanoparticle (GLDFe/Z-FA) can release its active ingredients in the slightly acidic environment of the tumor, triggering a series of biochemical reactions¹⁰⁸ (Fig. 9d).

Fig. 9 Investigation of Fe/ZIF-8-based nanoformulation distribution patterns in 4T1 tumor-bearing mice fluorescence imaging. (a) Fluorescence images of 4T1 tumor-bearing mice at different time points after intravenous injection of IR820 (I), IRFe/Z (II), and IRFe/Z-FA (III). (b) Ex vivo fluorescence images of harvested organs and tumors from 4T1 tumor-bearing mice at 24 h after injection. (c) Quantitative analysis of the mean fluorescence intensity in major organs and tumors in mice. (d) Synthesis process of GLDFe/Z-FA and synergistic mechanism of combining gas therapy, chemotherapy, and starvation therapy for drug-resistant tumor treatment.¹⁰⁸ Copyright 2023, American Chemical Society.

GLDFe/Z-FA induces a “starvation” state by reducing the glucose metabolism rate of tumor cells, thereby inhibiting the proliferation of tumor cells. At the same time, GOx catalyzes the oxidation of glucose to generate H₂O₂, and the iron ions in Fe/ZIF-8 further convert H₂O₂ into ˙OH through the Fenton reaction. These highly active free radicals directly induce cellular oxidative stress, leading to tumor cell death. Additionally, the platform effectively inhibits the expression of P-glycoprotein (P-gp) by oxidizing l-arginine to nitric oxide (NO), thereby increasing the accumulation of DOX in tumor cells and significantly enhancing the cytotoxic effect of chemotherapy. Combining these mechanisms, GLDFe/Z-FA not only produces therapeutic effects through CDT alone, but also achieves a significant improvement in comprehensive treatment through synergistic chemotherapy and gas therapy. In vivo experiments showed that the strategy had an inhibition rate of up to 73.02% on tumor growth, which was significantly better than the single treatment group, demonstrating the broad application potential of CDT-based multimodal treatment strategies in cancer treatment (Fig. 9(a–c)).

In addition, Wu et al. developed an innovative DOX-loaded ZIF-8/SrSe nanozyme construct (ZIF-8/SrSe@DOX), further enriching the exploration in this field.¹⁰⁹ This platform combines chemotherapeutic drugs with Fenton reaction catalysts, aiming to achieve synergistic therapeutic effects by simultaneously inducing apoptosis and ferroptosis. With its powerful GSH oxidase-like activity, ZIF-8/SrSe@DOX is able to oxidize GSH to glutathione disulfide (GSSG) in the tumor microenvironment, while inhibiting GPX4 and SLC7A11 proteins, thereby destroying the antioxidant system of tumor cells and inducing ferroptosis. In addition, the system further amplifies the therapeutic effect of CDT by regulating iron metabolism, which involves ferritin, transferrin receptor, and heme oxygenase (HO-1). The precise release of DOX not only triggers DNA damage, but also synergistically activates multiple mechanisms of apoptosis and ferroptosis. In in vitro and in vivo experiments, ZIF-8/SrSe@DOX achieved responsive drug release in the acidic environment of tumors and at high GSH levels, significantly inhibiting tumor growth while reducing therapeutic side effects, providing a novel and efficient strategy for the multimodal treatment of CDT.

4.2. Phototherapy: mechanism and ZIF-8 optimization

Tumor phototherapy represents an innovative method in the field of cancer treatment, which achieves therapeutic effects by using light energy to directly act on tumor cells. This method is mainly divided into PDT and PTT. In PDT, a specific PS is highly sensitive to light wavelengths. When irradiated with light of appropriate wavelengths, this PS can excite and produce large amounts of reactive oxygen species and other reactive compounds, thereby triggering tumor cell damage and apoptosis. Compared with PDT, PTT uses photothermal agents (PTA) to absorb light energy and convert it into heat energy, thereby directly destroying cancer cells by increasing the local temperature of the tumor.

However, despite the high therapeutic potential of these therapies, conventional photosensitizers and photothermal agents face multiple challenges in practical applications. These challenges include low stability, tendency to aggregate, and difficulty in being internalized by cells, which limit the efficiency and breadth of its clinical application. To overcome these limitations, researchers have developed nanotechnology-based systems to optimize the delivery and effectiveness of these therapeutics. Among these nanosystems, ZIF-8 has shown great potential as a nanocarrier. In this way, the stability and cellular internalization efficiency of therapeutic agents can be significantly improved, thereby pushing phototherapy toward a higher level of clinical application (Fig. 10).

Fig. 10 Photothermal therapy efficiency and optimization strategies.

4.2.1. Avoiding PS accumulation and reducing the hypoxia environment to improve the efficacy of PDT. To address the challenges of PS self-aggregation and TME hypoxia in traditional PDT, researchers have developed innovative nanotechnology strategies targeting key cancer mechanisms. For instance, tumor hypoxia, a hallmark of cancer progression resulting from rapid tumor growth and insufficient vascularization, is a critical barrier to effective PDT. Additionally, PS self-aggregation reduces photodynamic efficiency by diminishing singlet oxygen generation, which is crucial for inducing oxidative damage and subsequent cancer cell death.

In one study, Xu et al. utilized the microporous structure of ZIF-8 as a molecular cage to uniformly encapsulate the hydrophobic PS zinc phthalocyanine (ZnPc) using a co-precipitation method. By preventing ZnPc self-aggregation, this approach maintained efficient cytotoxic singlet oxygen production under 650 nm light, targeting cancer cells' oxidative stress pathways. Optimizing ZnPc loading further minimized aggregation within ZIF-8 micropores, enhancing the nanosystem's photodynamic activity. This ZnPc@ZIF-8 platform demonstrated significant in vitro efficacy by directly inducing oxidative stress-mediated apoptosis in cancer cells.¹¹⁰

In another study, Sun et al. developed Ce6@ZIF-8 composites by incorporating hydrophobic chlorine e6 (Ce6) into the ZIF-8 matrix through a one-pot method. To counteract tumor hypoxia—a condition promoting cancer cell survival and resistance to treatment—they loaded bovine serum albumin (BSA)–MnO₂ nanoparticles with catalase-like activity onto the surface of ZIF-8. The resulting BSA-MnO₂/Ce6@ZIF-8 system generated oxygen within the acidic, H₂O₂-rich TME, enhancing ROS production and PDT efficacy. This strategy effectively disrupted the hypoxic environment and weakened cancer cells' metabolic resilience under low-power 650 nm light irradiation.¹¹¹

Furthermore, Ma et al. embedded gold nanoparticles (AuNPs) with catalase-like nanozyme properties onto ZIF-8 surfaces while encapsulating Ce6 within. Under 660 nm laser irradiation, this oxygen-generating nano-delivery system increased singlet oxygen production, intensifying oxidative damage to tumor cells. By targeting the hypoxic cores of solid tumors, this system achieved a remarkable tumor growth inhibition rate of 94.1%, demonstrating the ability to exploit TME vulnerabilities.¹¹²

These advancements not only resolved PS self-aggregation but also addressed hypoxia-driven resistance mechanisms in the TME, significantly enhancing PDT's adaptability and efficacy. By leveraging the unique properties of the TME, such as acidity and oxidative imbalances, these nanoplatforms provide a precise, mechanism-driven approach to improve cancer therapy. Additionally, the therapeutic platform shown in Fig. 11 also demonstrates further improvements in cancer treatment.

Fig. 11 ZIF-8 nanoplatforms for dual cancer therapy. (a) ZIF-8 nanoplatforms for CT/PDT.¹¹³ Copyright 2020, Theranostics. (b) ZIF-8 nanoplatforms for CDT/PTT¹¹⁴ Copyright 2018, Elsevier. (c) ZIF-8 nanoplatforms for CT/PDT.¹¹⁵ Copyright 2020, American Chemical Society.

4.2.2. Inhibition of the expression of HSPs to improve the therapeutic effect of PTT. In PTT, tumor cells often adapt to heat stress through the upregulation of heat shock proteins (HSPs), a defense mechanism that helps maintain protein stability and resist apoptosis under thermal stress. This adaptive response poses a significant challenge to PTT efficacy, as it diminishes heat-induced cytotoxicity. To address this, Lei et al. developed an innovative nanoparticle platform, ZIF-8@GA, which integrates dihydroartemisinin (DHA), GOx, and AuNPs into ZIF-8. This platform is designed to exploit the unique TME, characterized by low pH, elevated glucose levels, and high ROS, to achieve targeted drug delivery and enhanced therapeutic effects.⁴⁵

The ZIF-8@GA nanoparticles actively interfere with multiple pathways in the osteosarcoma tumor microenvironment. GOx catalyzes the conversion of glucose into gluconic acid and H₂O₂, amplifying ROS production. Elevated ROS levels subsequently promote dihydroartemisinin-induced lipid peroxidation (LPO) and trigger ferroptosis, an iron-dependent form of cell death. This mechanism effectively disrupts the antioxidant defense systems of tumor cells, including glutathione depletion, making them more vulnerable to oxidative stress. Simultaneously, high ROS levels and LPO inhibit the expression of HSPs, undermining the heat resistance of tumor cells and enhancing the cytotoxicity of PTT.

By targeting these cancer mechanisms, ZIF-8@GA not only leverages ROS to induce ferroptosis but also suppresses HSP-mediated thermotolerance, creating a dual therapeutic effect. In vivo experiments demonstrated that ZIF-8@GA combined with near-infrared (NIR) irradiation (10 minutes per day) significantly inhibited tumor growth compared to monotherapies. The physical pathway of heat-induced cell destruction through PTT, coupled with the chemical pathway of ROS-mediated ferroptosis and HSP inhibition, highlights the multimodal efficacy of this strategy.

This study underscores the potential of combining ferroptosis induction with PTT to counteract the adaptive mechanisms of tumor cells. By integrating chemical and physical approaches to disrupt key tumor-promoting pathways, ZIF-8@GA provides a robust platform for osteosarcoma treatment, offering promise for a broader range of clinical applications in addressing therapy-resistant cancers.

4.2.3. Combination therapy based on PDT and PTT. Cancer progression is closely associated with a unique TME characterized by hypoxia, high GSH levels, and acidity—conditions that often hinder the efficacy of conventional therapies. Combining PDT and PTT has emerged as a promising strategy to address these challenges by exploiting TME properties and inducing synergistic therapeutic effects. Table 6 shows the research progress on the application of ZIF-8 nanoparticles in combined cancer therapy based on PDT and PTT.

Table 5 Modification methods and applications of ZIF-8 in drug delivery systems: a comprehensive analysis

Modification methods	Advantages	Disadvantages	Applications
Targeted delivery	Precise drug delivery and reduced damage to normal tissue	Requires sophisticated synthetic steps and techniques	Targeting tumor cells with specific receptors, e.g., high folate receptor expression in cancer cells
Controlled release	Precise control of drug release behavior	Limited by external stimuli, stability and controllability concerns	Intelligent release systems that respond to environmental conditions such as pH, temperature, and light
Doped with Fe or Mn	Enhanced magnetic properties, suitable for magnetic field-assisted targeted drug release	Complex preparation steps required	Magnetic response and photosensitivity in drug release systems
Doped with Cu	Enhanced loading and release properties of the drug	Reaction conditions need to be optimized	Improves drug stability and functionality
Doped with Ag or Au	Improved antibacterial properties	Special preparation techniques are required	Good drug loading capabilities with enhanced antibacterial properties
Bionic mineralised	Controls the shape, size, and surface properties of ZIF-8 crystals	Deposition conditions need to be controlled for directional control	Suitable for enhancing the stability and functionality of biological macromolecules
Core–shell	Highly controllable carrier performance	Multi-stage preparation required to construct the core–shell structure	Suitable for combining drug protection and release, used in nanodrug delivery

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Table 6 Research progress on the application of ZIF-8 nanoparticles in combined cancer therapy based on PDT and PTT

Nanocomposites	Payloads	Animal models/cancer cell types	Key factors	Applications	Ref.
CaO2/ICG@ZIF-8	ICG: PSs	4T1 breast cancer mouse/4T1 cells	1. CaO2: increases tumor tissue O2 levels and consumes GSH	PDT and PTT	116
			2. ICG: enhanced photothermal therapy through high light-to-heat conversion efficiency (η = 44%)
ZCNs	ZIF-8	Nude mice bearing A549 tumors/A549 cells	1. Effective enhancement of combined photothermal and photodynamic cancer therapy under the guidance of photoacoustic imaging	PTT and PDT	117
AR-ZS/ID-P	ICG: PS, DOX: chemotherapeutic drug	MCF-7 tumor models of mice/MCF-7 cells	1. AR: enhances its tumor targeting ability	PDT, PTT, and CT	118
			2. ICG/DOX: efficient (>95%) loading of ICG and DOX, achieving controlled release in an acidic tumor environment through pH sensitivity
			3. Multimodal treatment scheme: combining ICG-supported PDT and PTT with DOX's CT to achieve triple-mode efficient treatment and reduce side effects
ZIF-8@Ce6–HA	Ce6: PSs	Female BALB/c mice/HepG2 cells	1. ZIF-8: overcomes the limitation of free Ce6 being easy to aggregate, thus improving the efficiency of PDT	PDT	119
			2. HA: improves the stability and biocompatibility of ZIF-8 and prolongs blood circulation time
ZnS@ZIF-8/ICG/TPZ	ICG: PS, TPZ: chemotherapeutic drug	Male Balb/c nude mice/Huh7 cells	1. H2S: not only is it cytotoxic, but it can also enhance intracellular ROS by downregulating CAT expression	PDT and CT	113
			2. TPZ: It is activated under hypoxic conditions and increases cell killing
			3. A ZSZIT nanoplatform that can achieve synergistic effects of chemical and photodynamic therapy was constructed
ZDZP@PP	DOX: chemotherapeutic drug; PpIX: PS	4T1 tumor-bearing BACB/C mice/4T1 cells	1. By encapsulating DOX in the ZIF-67 core and PpIX in the ZIF-8 shell, independent encapsulation and sequential release of drugs were achieved, effectively controlling the interaction between drugs	PDT and CT	115
			2. Using a ZIF-67 core, a ZIF-8 shell, and a PDA-PEG layer, a multilayered nanoplatform was created that possessed the capabilities of pH-triggered drug release and hydrogen peroxide-responsive oxygen generation
CoFe2O4@PDA@ZIF-8	DOX, CPT: chemotherapeutic drugs	Tumor-bearing mice/HepG2 cells	1. CoFe2O4: acts not only as a T2-weighted MRI probe, but also as a PTT reagent and drug carrier, enhancing the dual functions of imaging and treatment	PTT and CT	120
			2. PDA: protects DOX from premature leakage and responds to pH and NIR dual stimulation for controlled release

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Zhang et al. developed an innovative oxidative stress amplifier, CaO₂/ICG@ZIF-8, that simultaneously addresses hypoxia and GSH overexpression in the TME. They used ZIF-8 as a nanocarrier to encapsulate CaO₂ and ICG in uniformly sized nanoparticles (∼215 nm hydrated size). In the acidic environment unique to tumors, CaO₂ reacts with water to generate oxygen, alleviating hypoxia—a key barrier to effective PDT.¹¹⁶ Furthermore, CaO₂ reacts with GSH to generate glutathione disulfide (GSSH), which depletes the antioxidant capacity of cancer cells and maintains elevated levels of ROS. These ROS induce oxidative damage, thereby enhancing PDT efficacy. In addition, the photothermal conversion efficiency of this platform is about 44%, enabling PTT to further damage cancer cell viability through high temperature treatment. By amplifying oxidative stress and exploiting the vulnerability of the TME, CaO₂/ICG@ZIF-8 exhibits excellent therapeutic effects in both in vitro and in vivo cancer models, providing a powerful solution to overcome tumor adaptation mechanisms.

Deng et al. synthesized iridium dioxide nanoparticles (IrO₂ NPs) with catalase-like activity and significant PTT functionality. These nanoparticles were modified with ZIF-8 shells and further functionalized with bovine serum albumin-folate (BSA-FA) for targeted delivery to tumor cells. The nanoplatform combines photothermal heating (a conversion efficiency of 62.1%) with ROS-mediated apoptosis induced by the PS Ce6.¹²¹IrO₂ NPs mimic catalase activity by converting endogenous H₂O₂ into oxygen, alleviating TME hypoxia and enhancing PDT. Meanwhile, the photothermal effect of PTT increases the permeability of tumor cell membranes, promotes ROS diffusion and maximizes cytotoxicity. By targeting key features of the TME, including hypoxia and antioxidant defense, IrO₂@ZIF-8/BSA-FA achieves a high synergistic effect with superior tumor inhibition compared to monotherapy in preclinical models.

Both CaO₂/ICG@ZIF-8 and IrO₂@ZIF-8/BSA-FA demonstrate the potential for combining PDT and PTT to overcome the challenges of TME adaptability in cancer progression. By addressing hypoxia, depleting GSH, and inducing ROS-mediated apoptosis, these platforms directly target cancer-promoting mechanisms such as metabolic reprogramming and oxidative stress resistance. The integration of PTT and PDT pathways creates a powerful multimodal strategy that significantly improves therapeutic specificity and efficacy.

4.3. Challenges in other cancer therapies and ZIF-8-based optimization strategies

4.3.1. Immunotherapy. While immune checkpoint inhibitors (ICIs) have demonstrated remarkable clinical efficacy in cancer treatment, their success is often limited by challenges such as low tumor immunogenicity and the immunosuppressive TME, which enable immune evasion and suppress immune cell activation, resulting in suboptimal therapeutic outcomes. In this context, ZIF-8 has emerged as a multifunctional therapeutic platform, addressing these challenges through its high specific surface area, porous structure, and pH-responsive decomposition properties, which enable efficient delivery of anti-cancer drugs, immunomodulators, and tumor antigens. Upon decomposition in the acidic TME, ZIF-8 releases Zn²⁺ ions that disrupt cancer cell homeostasis by triggering intracellular ion shifts and osmotic pressure changes, while simultaneously promoting macrophage polarization, immune cell recruitment, and T cell activation, thereby enhancing anti-tumor immune responses. Notably, Ding et al. developed a Pluronic F127-modified ZIF-8 nanoparticle (^F127ZIF-8_CCCP) capable of inducing immunogenic cell death through the caspase-1/gasdermin D (GSDMD) pathway, known as pyroptosis, which not only eliminates tumor cells but also releases damage-associated molecular patterns (DAMPs) to further stimulate immune activity in the TME; this process is amplified by mitochondrial stress induced by the carbonyl m-chlorophenylhydrazone (CCCP) loaded in the nanoparticles.¹²² Furthermore, Sun et al. addressed the immunosuppressive effects of mutant p53 (mutp53) on the cGAS-STING pathway by developing a Mn-Zn dual-ion delivery system (ZIF-8@MnO₂), which releases Zn²⁺ to promote mutp53 degradation and Mn²⁺ to enhance cGAS sensitivity to immunostimulatory signals, thereby activating anti-tumor immunity and synergizing with PD-L1 checkpoint blockers to inhibit tumor growth and metastasis in breast cancer models.¹²³ As illustrated in Fig. 12(a), the therapeutic efficiency of ZIF-8@MnO₂ nanoparticles in vivo demonstrates their potential in enhancing anti-tumor responses. Collectively, these studies underscore the potential of ZIF-8-based platforms to overcome the limitations of conventional ICIs by leveraging precise drug delivery, TME modulation, and immune activation to address immune escape mechanisms, low immunogenicity, and genetic mutations such as mutp53, providing a robust foundation for next-generation cancer immunotherapy.

Fig. 12 (a) Therapeutic efficiency of ZIF-8@MnO₂ nanoparticles in vivo.¹²³ Copyright 2024, Wiley. (b) CLSM images of different NP-treated 4T-1 cells colabeled with 0.5 μM DAPGreen.¹²⁴ Copyright 2022, American Chemical Society. (c) In vivo demonstration of the combined antitumor therapy of the PSZ nanosystem.¹²⁵ Copyright 2024, American Chemical Society. (d) Tumor volume changes after post-treatment in 14 days.¹²⁶ Copyright 2021, Elsevier. (e) Changes in body weights during 15 days of treatment are plotted.¹²⁷ Copyright 2024, Royal Society of Chemistry.

4.3.2. Starvation therapy. ST is an innovative anticancer strategy that inhibits tumor growth by depriving cancer cells of essential nutrients and energy. Given that tumor cells are highly dependent on intracellular glucose levels and rely on active aerobic glycolysis for survival and proliferation, ST effectively suppresses tumor development by accelerating glucose consumption. Moreover, autophagy, a key mechanism for maintaining cellular homeostasis, plays a dual role in cancer, either promoting survival under nutrient deficiency or contributing to cancer cell death when disrupted. The advent of nanotechnology has provided novel opportunities to regulate autophagy and glucose metabolism, offering new directions for cancer therapy. In this context, ZIF-8 has emerged as a promising platform for starvation therapy due to its unique structural and functional properties.

As a metal–organic framework material with a high specific surface area and porous architecture, ZIF-8 can efficiently load anticancer agents, such as GOx, and release them responsively within the acidic tumor microenvironment. This capability enables ZIF-8 to induce a “starvation” state in tumor cells by regulating glucose metabolism, triggering oxidative stress, and disrupting intracellular ion balance through Zn²⁺ release, thereby enhancing cell apoptosis and amplifying anti-tumor effects. For instance, Li et al. developed mCG@ZIF, a novel cell membrane-coated ZIF-8 nanoparticle loaded with CQ and GOx.¹²⁴ This platform synergistically integrates starvation therapy with autophagy regulation to maximize therapeutic efficacy. GOx promotes glucose depletion, inducing autophagy as a survival mechanism in cancer cells, while CQ inhibits the pro-survival autophagic pathway, disrupting cellular adaptation to nutrient deprivation and enhancing the cytotoxic effects of glucose starvation. Additionally, the system catalyzes glucose hydrolysis to generate H₂O₂, further contributing to tumor cell death. As shown in Fig. 12(b), CLSM images of different NP-treated 4T-1 cells colabeled with 0.5 μM DAP Green provide visual evidence of the cellular uptake and therapeutic effects of these nanoparticles.

Recent findings also highlight lactate as a key metabolic target, particularly under glucose-deprived conditions, where it serves as an alternative energy source in mitochondria. Targeting both glucose and lactate metabolism has therefore become a dual strategy for optimizing ST. Yu et al. developed CHC/GOx@ZIF-8, a ZIF-8-based nanomedicine co-delivering α-cyano-4-hydroxycinnamate (CHC) and GOx. CHC blocks lactate influx and alleviates tumor hypoxia, enhancing GOx catalytic activity and inducing glucose consumption and H₂O₂ accumulation.²⁸ This dual-deprivation approach significantly increased the apoptosis rate to 71.7% in vitro and demonstrated robust tumor suppression in vivo, underscoring the synergistic potential of targeting both glucose and lactate metabolism.

In summary, ZIF-8, as a therapeutic platform for starvation therapy, offers a versatile approach to precisely control drug release, modulate tumor metabolic pathways, and integrate multiple therapeutic mechanisms. By leveraging its structural advantages and functional versatility, ZIF-8 provides strong support for the application of nanotechnology in starvation therapy, paving the way for more effective and targeted cancer treatments.

4.3.3. Gene therapy. siRNA-induced cancer GT represents a promising and precise approach for cancer treatment by selectively silencing or eliminating key oncogenes in cancer cells. Despite its potential, the clinical application of naked siRNA faces significant challenges, including rapid enzymatic degradation, low transfection efficiency, and non-specific biodistribution, which limit its therapeutic efficacy. To address these limitations, ZIF-8 has emerged as an ideal nanoplatform for gene therapy due to its high specific surface area, excellent biocompatibility, and pH-responsive properties. ZIF-8 effectively protects siRNA from nuclease-mediated degradation in circulation and releases siRNA responsively in the acidic tumor microenvironment, enhancing its stability and transfection efficiency within cancer cells.

Additionally, the porous structure of ZIF-8 provides the capacity to co-load other therapeutic agents, such as chemotherapeutic drugs or photothermal agents, enabling multifunctional synergistic treatment. This feature facilitates precise spatiotemporal control over siRNA release, achieving targeted gene therapy while minimizing systemic toxicity and off-target effects. Feng et al. advanced this concept by developing a multifunctional nanoplatform, PDA-ZIF-8 (PZ), which integrates siRNA delivery with PTT under the guidance of dual-modal photoacoustic (PA) and near-infrared (IR) imaging. This innovative platform allows for non-invasive imaging and precise treatment. Experimental results demonstrated that PZ significantly increased cancer cell apoptosis rates from 13.35% to 22.78% under 808 nm light irradiation, highlighting the enhanced anti-cancer efficacy of the PTT-GT combination strategy (Fig. 12(c)).¹²⁵The integration of PA/IR imaging further enhances therapeutic precision by providing real-time diagnostic capabilities, ensuring selective tumor cell elimination while sparing healthy tissues. This non-invasive imaging-guided therapeutic approach represents a significant advancement in cancer treatment, addressing key limitations of conventional siRNA delivery systems. By combining PA/IR imaging-guided PTT with GT in a compact nanosystem, ZIF-8-based platforms offer a highly synergistic and versatile approach for multimodal cancer therapy, paving the way for more effective and personalized treatment strategies.

4.3.4. Peptides and radiotherapy. In recent years, ZIF-8-based nanoplatforms combined with peptide molecules and radiosensitizers have shown great potential in cancer treatment, effectively improving therapeutic effects through multiple mechanisms. As short-chain amino acid structures (3–5 kDa), peptides have higher cell membrane permeability and lower immunogenicity than antibodies (150 kDa) and can target intracellular transcription factors, oncogenic factors, and enzymes, and specific drug delivery is achieved through precise binding to tumor vasculature.¹²⁸ In addition, peptide synthesis and modification are simple, low-cost, have low patent barriers, and are easy to be clinically transformed. Radiotherapy induces irreparable DNA damage in tumor cells by directly damaging DNA molecules or indirectly generating ROS, but hypoxia and high expression of GSH in the TME often weaken the radiation therapy effects. To address this problem, Fu et al. developed PEG-mediated ZIF-8 NPs to co-deliver DOX and the H4R4 peptide, which significantly enhanced the drug's cytotoxicity by promoting endosomal/lysosomal escape¹²⁶ (Fig. 12(d)); Hananeh et al. designed and developed Cs-g-PCL-coated ZIF-8 (Zn, Fe) BMOFs and combined them with the TAT peptide to achieve targeted delivery and pH-responsive release to improve the therapeutic effect of lung cancer;¹²⁹ Pan et al. developed an FA-Mn₃O₄@ZIF-8 nanoradiation sensitizer, which, through X-ray excitation, relieves tumor hypoxia, consumes GSH and increases ROS generation, significantly improving the radiotherapy sensitivity of cervical cancer;¹³⁰ the Apt-PEG-DOX/ZIF-8@GQD nanosystem constructed by Iranpour et al. releases doxorubicin and graphene quantum dots (GQDs) to enhance X-ray absorption and achieve synergistic effects of chemotherapy, radiotherapy and targeted therapy¹²⁷(Fig. 12(e)). In summary, the ZIF-8-based nanoplatform combined with the intracellular targeting properties and radiosensitization mechanism of peptides overcomes the radioresistance caused by the tumor microenvironment and provides a new cancer treatment strategy that is precise and efficient and has clinical translational potential. In addition, Table 7 shows the latest research results on customized tumor therapy based on the ZIF-8 nanoplatform.

Table 7 The latest research results on customized tumor treatment based on the ZIF-8 nanoplatform

Applications	Nanocomposites	Animal models/cancer cell types	Key factors	Ref.
IMT	(M + H)@ZIF/HA	4T1 tumor-bearing mice/4T1 cells	1. Cell pyroptosis mechanism: HYD upregulates GSDME expression, and MIT activates caspase-3, which together promote the transformation of cells from apoptosis to pyroptosis	131
			2. Anti-MDSC immune escape: the nanoplatform triggers the transformation of cell apoptosis to pyroptosis, while destroying the MDSC-mediated immune escape mechanism
			3. Long-term immune memory: convert cold tumors into antigen reservoirs, strengthen immune responses, inhibit immune escape, and establish long-term immune memory responses against metastasis
	α-Galcer/DOX@ZIF-8@HA	Male C57BL/6 mice/Hepa1–6 cells	1. NKT cell activation triggers IFNγ production and cytotoxicity, activating other immune cells (such as NK cells and CD8+ T cells)	132
			2. NKT cell-mediated immunotherapy is implemented in the treatment of hepatocellular carcinoma, enhancing the anti-tumor effect by activating immune cells and combining the cytotoxic effect of DOX
	CUR-BMS1166@ZIF-8@PEG-FA	K7M2 tumor-bearing mice/K7M2 cells	1. Using Cur and BMS1166 to activate autophagy and block PD-1/PD-L1 interaction	133
			2. By activating autophagy and inducing immunogenic cell death, “cold” tumors can be transformed into “hot” tumors, enhancing the immunotherapy effect of OS
	^F127ZIF-8CCCP	4T1 tumor-bearing BALB/c mice/4T1 cells	1. Inducing pyroptosis through a GSDMD-dependent pathway contributes to in situ immune priming	122
			2. Activating anti-tumor immunity and reprogramming the immunosuppressive TME by recruiting immune cells and promoting macrophage polarization, thereby achieving efficient tumor growth inhibition
ST	AQ4N/GOx@ZIF-8@CM	Female Balb/c mice bearing HepG2 tumors/LO2, HepG2 cells	1. GOx is used to deplete glucose and oxygen, and when combined with the hypoxia-activated prodrug AQ4N, cascade amplification of starvation therapy and chemotherapy is achieved	134
			2. Cancer cell membrane camouflage gives the biomimetic nanoreactor homotypic targeting and immune escape characteristics, prolonging blood circulation time
	Mem@GOx@ZIF-8@BDOX	4T1 tumor-bearing mice/4T1 cells	1. Cut off the glucose supply through GOx and achieve amplified chemotherapy through the H2O2 sensitive prodrug BDOX	135
			2. Possess immune evasion and homotypic binding ability and enhance tumor preferential accumulation and uptake
CT	RAPA@ZIF-8	MCF-7/ADR-xenografted NOD/SCID mice/MCF-7/ADR cells	1. Combining the drug release properties of ZIF-8 with the mTOR inhibitory effects of rapamycin to enhance tumor responsiveness to chemotherapy	136
	PBD@ZIF-8	CT26 tumor/CT26 cells	2. Combined with low-toxic precursors, in situ synthesis triggered by ultrasound (US) at the tumor site to produce chemotherapeutic agents	137
	HA/ZIF/DQ	BALB/c nude mice bearing HepG2/ADR tumors/HepG2 cells	3. Used in cancer treatment, especially for cancer cells that overexpress CD44 receptors, to enhance the ability of drugs to reach deep tumor tissues	138
GT	Apt-PEG-siRNA@ZIF-8	C57BL/6 mice/PC-3, HEK-293 cells	1. Reduction of SNHG15 expression by siRNA-mediated gene silencing inhibits cell proliferation and colony formation and promotes cell apoptosis	50
			2. Reduced survival and tumor growth in prostate cancer cells, providing a potential therapeutic strategy
RT	Apt-PEG-DOX/ZIF-8@GQD	C57BL/6 mice/HT-29 cells, CHO cells	1. Enhanced X-ray absorption and synergistic anti-tumor effects in the presence of radiotherapy	127
			2. Significant tumor suppression with minimal side effects in animal models

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5. Conclusions and outlook

The application of ZIF-8 in drug delivery and tumor therapy represents an important breakthrough in addressing long-standing challenges such as poor drug solubility, low chemical stability, and nonspecific targeting. The porous structure, high specific surface area, and tunable biocompatibility of ZIF-8 make it an ideal drug carrier. Through a series of innovative strategies, such as atomic doping, surface functionalization and the addition of targeting molecules (such as folic acid, hyaluronic acid, polyethylene glycol, etc.), the performance of ZIF-8 has been significantly improved; it not only improves drug delivery efficiency, but also enables responsive release to the tumor microenvironment, thereby maximizing therapeutic efficacy while significantly reducing systemic toxicity. This personalized drug release mechanism lays the foundation for targeted therapy, especially providing a new idea for complex cancer treatment.

Looking to the future, ZIF-8 holds great promise in clinical settings, but there are still several key areas that require further research. First, optimizing the synthesis method of ZIF-8 to improve its large-scale production and reproducibility will be key to achieving clinical translation. Although existing laboratory synthesis technologies are effective, they require further optimization to meet strict pharmaceutical manufacturing standards and ensure their consistency and safety in large-scale production. In addition, although ZIF-8 has excellent performance in drug loading and biocompatibility, its long-term behavior in the body, interaction with biological tissues, and degradation and excretion pathways after drug delivery still require further study. This will help evaluate whether ZIF-8 accumulates in the body, whether it may cause potential toxicity, and how to ensure its safety and effectiveness in long-term treatment regimens.

Another area of concern is the use of ZIF-8 in combination therapies. Since ZIF-8 can simultaneously load multiple therapeutic agents, it shows great potential in multimodal treatment strategies combining chemotherapy, photodynamic therapy, photothermal therapy, and immunotherapy. This comprehensive treatment approach can effectively deal with drug-resistant or recurrent cancers through synergy, significantly improving treatment outcomes. The versatility of ZIF-8 not only enables it to serve as a drug delivery platform but also enhances tumor targeting and therapeutic efficacy by combining different treatment modalities. This feature opens up more possibilities for developing personalized cancer treatments.

Overall, ZIF-8's adaptable framework, easily modified structure, and versatility make it a highly promising candidate for next-generation drug delivery systems. Through continued interdisciplinary research and collaboration, ZIF-8 has the potential to transform from laboratory applications into clinical therapeutic tools. Future research not only needs to overcome the current technical bottlenecks, but also needs to fully tap the potential of ZIF-8 and promote its application in the treatment of complex diseases such as cancer. ZIF-8 is expected to revolutionize the treatment of difficult-to-treat diseases such as cancer, providing more precise, efficient and personalized therapies that meet patient needs. As research continues, the clinical application of ZIF-8 will significantly improve patient outcomes and is expected to become a revolutionary tool in the field of anti-cancer treatment in the next few decades. As we advance, the integration of ZIF-8 into clinically approved treatments holds the promise of significantly enhancing patient outcomes in the coming decades.

Author contributions

Wenyue Gao: conceptualization, analysis, investigation, and writing – original draft; Xinping Han: conceptualization and drawings, writing – original draft; Min Xu: writing – reviewing; Ling Li: writing – reviewing; Yan Xu: writing – reviewing; Zhu Gao: conceptualization; and Cuijuan Wang: investigation and resources.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge financial support from the National Natural Science Foundation of China (No. 21401151), Fundamental Research Funds for the Central Universities (No. 2682023ZTPY064) and Sichuan Provincial Administration of Traditional Chinese Medicine Project (No. Q115723S02001).

Notes and references

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