Advancements in Bimetallic Metal–Organic Frameworks for Oral Medicine

Abstract

The characteristic oral environment – with its dynamic clearance, moisture, microbial load, and inflammatory potential – makes oral diseases highly prevalent and therapeutically challenging. Metal-organic frameworks (MOFs), an emerging class of inorganic–organic hybrid porous coordination materials, have become pivotal in modern biomedical engineering due to their facile synthesis, high surface area, large loading capacity, exceptional ion storage capability, tunable composition and pore size, and pH-responsive behaviour. To further enhance their performance, bimetallic metal-organic frameworks (BMOFs) have been constructed by incorporating two metal ions with functionalized organic ligands. Leveraging synergistic multimetallic effects and structural tunability, BMOFs exhibit significant potential in biomedical applications, including antibacterial activity, catalysis, and drug delivery. Exploratory applications of BMOFs in the prevention and treatment of oral diseases have already emerged, spanning periodontitis management, caries prevention, oral tissue regeneration, and targeted cancer therapy. Nevertheless, challenges remain in terms of biosafety, long-term stability, in vivo degradation behaviour, and scalable fabrication. This review summarizes the synthesis strategies and functionalization approaches of BMOFs, the selection of metal pairs, and their synergistic mechanisms, with a focus on their applications in oral biofilm infections, inflammatory diseases, oromaxillofacial bone tissue engineering scaffolds, and cancer therapy. Additionally, it discusses current challenges related to biocompatibility, technical limitations, and the clinical translation of these technologies. By correlating the fundamental design principles of BMOFs with the diagnostic and therapeutic demands of oral diseases, this review aims to facilitate translational research and promote the development of BMOFs as innovative and efficient strategies for addressing a range of oral pathologies.

Graphical Abstract

Highlights

• •The synthesis methodologies, functionalization techniques, and mechanistic foundations of BMOFs are reviewed.
• •Integrating BMOFs with the specific therapeutic needs of oral diseases demonstrates the material’s innovative interdisciplinary applications.
• •The synergistic effects between the dual metal ions in BMOFs are underscored, demonstrating their potential for realising combined therapeutic modalities.
• •Extensive coverage of oral clinical applications.
• •A forward-looking perspective on clinical translation: addressing bottlenecks and solutions toward personalised precision oral medicine.

Introduction

The oral cavity, characterized by its dynamic, moist, and inflammatory ecosystem rich in microbes, presents a significant global health burden due to the high prevalence of chronic oral diseases.^1,2 These pathologies can be broadly categorized as follows: 1) bacterial diseases, primarily initiated by dental plaque biofilms³; 2) inflammatory conditions, closely linked to local immune dysregulation and inflammation-induced oxidative stress⁴; 3) neoplastic diseases; and 4) hard tissue defects resulting from trauma or tumour resection.5, 6, 7 Autologous bone grafting, while remaining the clinical gold standard for jaw reconstruction, is limited by donor site morbidity and insufficient bone supply.^8,9 Conventional therapies often face critical limitations, including incomplete removal of dental plaque biofilms, inadequate control of immune dysregulation and oxidative stress, and restricted tissue regeneration capacity.¹⁰ Consequently, there is an urgent need to develop novel biomaterials that integrate antibacterial and anti-inflammatory properties with the ability to modulate drug release and the local microenvironment, thereby addressing the complex therapeutic demands of oral diseases.¹¹

Metal-organic frameworks(MOFs), an emerging class of porous crystalline materials, have demonstrated considerable potential in biomedical applications owing to their high specific surface area, tunable pore architectures, and versatile surface chemistry.^12,13 However, materials intended for oral applications must contend with a challenging oral environment characterized by moisture, microbial flora, dynamic mechanical forces, and the need to combat pathogenic biofilms while promoting tissue regeneration. Although conventional monometallic MOFs exhibit promising functionalities, their practical utility in complex oral settings is often limited by a lack of functional diversity, insufficient stability, and restricted bioactivity. To address these limitations and enhance material performance for clinical translation, bimetallic metal-organic frameworks (BMOFs) have been developed as an advanced class of MOFs derivatives. BMOFs are constructed by coordinating two distinct metal ions or clusters with organic linkers. In addition to inheriting the structural advantages of conventional MOFs, the bimetallic synergy in BMOFs yields significantly enhanced properties, including increased catalytic active sites and improved structural stability.¹⁴ These characteristics render them highly promising for applications in catalysis and antibacterial therapy, offering innovative solutions for managing complex biological challenges in dental medicine.^15,16

In recent years, the programmable metal nodes and organic ligands of BMOFs have enabled multifunctional immunomodulatory capabilities beyond those of conventional monometallic MOFs.¹⁷ On the one hand, BMOFs can suppress the expression of pro-inflammatory cytokines, such as IL-6 and TNF-α, by inhibiting signalling pathways including NF-κB and the PI3K/AKT pathway. On the other hand, they modulate the activities of catalase and superoxide dismutase to scavenge reactive oxygen species (ROS) in situ, thereby restoring the redox-inflammatory balance in oral mucosal or periodontal tissues. Through rational synthesis, two distinct metal ions can be incorporated into a highly ordered framework with specific stoichiometric ratios and spatial arrangements. In certain cases, the introduction of a second metal ion can stabilize the oxidation state of the primary metal, enhancing the chemical and structural stability of the material under the complex oral environment – a critical feature for practical applications. Moreover, the pH-responsive degradation behaviour of BMOFs allows for triggered drug release specifically in acidic pathological sites, thereby minimizing nonspecific irritation to healthy oral mucosa.

Additionally, the porous structure of BMOFs enables efficient encapsulation and protection of natural bioactive molecules, overcoming limitations such as poor water solubility, short oral retention time, and susceptibility to enzymatic degradation in saliva. Surface modification with hyaluronic acid or chitosan further confers mucoadhesive and plaque-targeting properties, achieving a synergistic ‘carrier-drug-microenvironment’ therapeutic approach. These multifunctional and coordinated attributes underscore the considerable potential of BMOFs in oral biomedical applications.

This review begins by summarizing the synthetic strategies and functionalization approaches of BMOFs, with a focused discussion on their recent advances in oral antibacterial therapy, periodontitis management, hard tissue regeneration, and oral cancer treatment (Scheme 1). Prospects and challenges related to clinical translation are also examined. By facilitating translational research and promoting BMOFs as innovative and efficient therapeutic strategies for various oral diseases, this review aims to offer valuable insights and future directions for their application in oral medicine.

Scheme 1.

BMOFs: Synthesis and applications in oral medicine.

Synthesis of BMOFs

The spatial distribution of metals in BMOFs can be systematically classified into two primary configurations: solid-solution structures and core–shell structures. The former features an atomic-scale homogeneous distribution of metal species, forming a homogeneous solid solution, forming a homogeneous solid solution, whereas the latter demonstrates spatially partitioned metal arrangements, resulting in a heterogeneous core–shell architecture.¹⁸

Synthetic strategies for solid-solution structures include direct synthesis, post-synthetic metal exchange, and template-assisted methods. In contrast, core–shell structures are typically achieved through seed-mediated growth, selective post-synthetic exchange, or one-pot sequential synthesis, allowing precise interfacial control. These approaches enable fine-tuning of metal coordination kinetics and spatial distribution, providing systematic pathways for designing multifunctional BMOFs materials^19,20 (Figure 1).

Fig. 1.

Synthetic methods of BMOFs. a, Direct synthesis Copyright©2014, ACS-L.J. Wang.²¹ b, Post-synthetic metal ion exchange Copyright©2018, ACS-M.S. Denny.²² c, Template-assisted synthesis Copyright©2024, Royal Society Publishing-Y. Yuan.²³ d, Seed-mediated growth Copyright©2023, Elsevier-J. Cai.²⁴ e, Selective post-synthetic exchange Copyright©2012, RSC-X. Song.²⁵ f, One-pot stepwise synthesis Copyright©2019, Wiley-B. Li.²⁶

Solid-solution structures are typically synthesized via a straightforward one-pot co-precipitation method, which offers operational simplicity and high yield. However, improper metal ratios or suboptimal pH control may lead to the formation of impurity phases.²⁷ This configuration is well-suited for large-scale synthesis and catalytic/adsorption applications. In contrast, core-shell architectures exhibit enhanced design flexibility, enabling spatially segregated functionalities. When a continuous and uniform shell layer is achieved, a well-defined interface can be obtained.²⁸ Nevertheless, their synthesis generally involves a multi-step process requiring sequential layer-by-layer modification, resulting in greater operational complexity and reduced reproducibility. This structural design is particularly applicable to multifunctional integration and selective catalysis (Table 1).

Table 1.

Synthetic strategies for BMOFs.

Structure type	Synthesis method	Key features	Typical systems
Solid Solution Structure	Direct Synthesis	One-pot reaction of bimetallic precursors and ligands; requires matching of metal ion radii/coordination geometry; control of solvent/pH/temperature	MOF-74 series (Zn/Co, etc.), Zn/Co-ZIF-8
	Post-synthetic Metal Exchange	Soaking monometallic MOFs in a second metal salt solution; exchange kinetics governed by electronegativity differences and solvent effects	UiO-66(Zr) with Ti⁴⁺ exchange; Mn-MOF with Fe²⁺/Co²⁺ exchange
	Template Method	Use of polymers or sacrificial templates to guide directional metal incorporation; structure regulated via spatial confinement or coordination direction	Zn-polymer template for Zn/Ni-MOF-74; self-templated synthesis of hollow Zn/Ni BMOFs
Core–Shell Structure	Seed-Induced Growth	Epitaxial growth of a second MOF shell on a monometallic MOF seed; requires lattice matching or surfactant regulation	ZIF-8@ZIF-67; UiO-66@ZIF-8 (CTAB-controlled)
	Selective Post-synthetic Exchange	Selective replacement of surface metal nodes while retaining the core structure; requires control of reaction time/concentration to avoid over-etching	Zn-MOF@Cu-MOF (surface Zn²⁺ → Cu²⁺)
	One-Pot Stepwise Assembly	Stepwise assembly of core–shell structure based on differences in metal coordination rates; requires optimization of solvent, temperature, and addition sequence	Co/Zn-ZIF (Co²⁺ preferential nucleation); Cr/V-MIL-53@Cr-MIL-53 (microwave-assisted)

Bimetallic selection and synergistic mechanism

The precise selection and stoichiometric tuning of metal nodes represent a critical determinant of the physicochemical properties and biological functionalities of BMOFs^29,30 (Figure 2, Table 2).

Fig. 2.

Bimetallic systems in BMOFs.

Table 2.

Mechanisms of action and applications of bimetallic systems.

Bimetallic system	Synergistic mechanism	Biomedical applications	Key effects	Reference
Cu/Fe	Fe³⁺ catalyses the Fenton reaction, Cu²⁺ enhances electron transfer, synergistically promoting the generation of ROS	Tumour therapy, Antibacterial	Inhibits tumour growth better than cisplatin, effective antibacterial activity against S. aureus and E. coli	31,32
Zn/Mg	Zn²⁺ broad-spectrum antibacterial, Mg²⁺ activates immunity; Zn²⁺ promotes osteogenesis, Mg²⁺ promotes migration	Bone regeneration, Dental implants	Enhances antibacterial activity, angiogenesis, and bone regeneration; improves hydrophilicity/biocompatibility of PEEK-74 scaffolds	33,34
Mg/Cu	Mg²⁺ promotes osteogenesis, Cu²⁺ promotes angiogenesis; Cu²⁺ has antibacterial effects, Mg²⁺ has anti-inflammatory effects	Bone defect repair, Implant coatings	Osteogenesis-angiogenesis coupling effect, macrophage M2 polarization	35,36
Zn/Co	Mimics natural enzyme cascade antioxidant, Zn²⁺/Co²⁺ activate the Wnt pathway to promote osteogenesis/chondrogenesis	Periodontitis, Osteoarthritis	Reduces osteoclasts, promotes alveolar bone/subchondral bone regeneration, establishes an anti-inflammatory microenvironment	37,38
Cu/Zn	Cu²⁺ catalyses •OH generation, Zn²⁺ assists; Cu⁺ in situ drug synthesis + Zn²⁺ activates DNAzyme	Antibacterial, Cancer therapy	Multistage antibacterial, precise cancer treatment	39,40
Fe/Ni	Synergy between Fe³⁺’s Fenton activity and Ni’s electron regulation enhances peroxidase-like activity and electrochemical signals	Biosensing, Glucose monitoring	Detection limit down to 69 pg/mL, high sensitivity for H₂O₂ detection	41,42

The Cu/Fe BMOFs system

Copper and iron, two transition metal elements abundantly present in biological systems, have been increasingly incorporated into MOFs to construct bimetallic systems due to their crucial roles in redox reactions and the regulation of metalloenzyme activity.⁴³ Structurally, Cu/Fe BMOFs typically feature a synergistic coordination where Fe³⁺ drives Fenton reactivity and Cu²⁺ enhances electron transfer, collectively boosting ROS generation.³¹

Within acidic tumour microenvironments, these materials efficiently catalyse the decomposition of hydrogen peroxide into hydroxyl radicals, exhibiting superior •OH generation capacity and oxidative damage effects compared to monometallic analogues. Beyond the classical Fenton reaction, Cu/Fe BMOFs also deplete glutathione and promote lipid peroxidation, thereby activating ferroptosis and cupric-dependent apoptosis pathways.^44,45 In the 4T1 breast cancer mouse model, this material combines favourable biocompatibility with significant tumour-suppressing potential.⁴⁶

In antimicrobial applications, Cu/Fe BMOFs exhibit potent peroxidase-like activity, generating sufficient ROS even at low H₂O₂ concentrations to disrupt bacterial membranes and biofilms. They demonstrate significantly enhanced efficacy against pathogens such as Staphylococcus aureus and Escherichia coli compared to single-metal frameworks and maintain stable activity in simulated wound environments, offering a promising strategy against antibiotic-resistant infections.³²

The Zn/Mg BMOFs system

The Zn/Mg BMOFs system demonstrates significant advantages in biomedical applications through unique synergistic mechanisms.⁴⁷ Its functional principles are primarily manifested in three aspects. Firstly, Zn²⁺ exerts broad-spectrum antibacterial effects by disrupting bacterial membrane integrity and inhibiting key metabolic enzymes, while Mg²⁺ enhances innate immunity through the upregulation of host defense peptides. Their combination leads to a notable improvement in antibacterial efficacy.35, 48, 49 Secondly, in the context of preclinical bone regeneration models, Zn²⁺ upregulates the expression of ALP and OCN via the Wnt/β-catenin signalling pathway, whereas Mg²⁺ promotes osteoblast migration through the activation of the TRPM7 channel and optimizes the mineralization microenvironment by modulating local pH.50, 51, 52 Thirdly, Samy Selim et al³³ first synthesized a novel Zn-Mg-MOF74, composed of Zn²⁺, Mg²⁺, and 2,5-dihydroxyterephthalic acid (DHTA). This material exhibits a highly ordered three-dimensional porous structure and favourable biocompatibility, along with remarkable antibacterial activity against various pathogens, including Klebsiella pneumoniae and Escherichia coli. In a further study, Xiao et al³⁴ constructed a Zn-Mg-MOF74 coating on polyetheretherketone (PEEK) surfaces, resulting in a composite PEEK-74 scaffold. Their vitro studies findings confirmed that the Zn-Mg-MOF74 coating not only enhanced the antibacterial performance, biocompatibility, and hydrophilicity of the PEEK scaffold but also enabled controlled drug release, effectively promoting angiogenesis and bone tissue regeneration. This system offers a promising approach for repairing bone defects.

The Mg/Cu BMOFs system

The Mg/Cu BMOFs coating enables multifunctional biomedical applications through a unique bimetallic synergistic mechanism, which operates primarily through four aspects: controlled degradation and ion release, osteogenesis-angiogenesis coupling, antibacterial and immunomodulatory effects, and structure-function integration.53, 54, 55 By precisely tuning the Cu/Mg ratio, the crystal structure of the MOFs exhibits a gradient evolution, transitioning from a sheet-like to a rod-like morphology with increasing Cu content, enabling the sustained release of Mg²⁺ and Cu²⁺ ions.

In terms of osteogenic-angiogenic synergy, Mg²⁺ enhances ALP activity and upregulates OCN expression in pre-osteoblastic MC3T3-E1 cells via the PI3K/Akt signalling pathway, while Cu²⁺ promotes endothelial tubule formation through the HIF-1α/VEGF pathway. The bimetallic synergy results in the concurrent upregulation of Runx2 and COL1α1 gene expression, leading to a pronounced coupled osteogenic and angiogenic effect.³⁶

The antibacterial and immunomodulatory mechanisms involve Cu²⁺-mediated ROS generation via Fenton-like reactions, which disrupt bacterial membrane integrity, coupled with Mg²⁺-driven polarization of macrophages toward the M2 phenotype and suppression of the pro-inflammatory cytokine TNF-α.³⁵ Structurally, the microporous framework formed by organic ligands enables sustained release of growth factors, while the electronic transfer at Mg/Cu heterogeneous interfaces enhances catalytic activity. Surface hydroxylation reduces the contact angle and significantly improves cell adhesion.

Overall, this system achieves a ternary balance among degradation kinetics, bioactivity, and antibacterial performance through precise control of the metal ratio.

The Zn/Co BMOFs system

Zn/Co BMOFs represent a class of multifunctional nanomaterials that combine antioxidative, anti-inflammatory, and osteogenic properties, demonstrating significant therapeutic potential in the treatment of inflammatory bone-related disorders such as periodontitis and osteoarthritis. Periodontitis, a chronic inflammatory disease triggered by bacterial infection, is characterized by the pathological accumulation of ROS in local tissues. Excessive ROS not only causes cellular damage but also inhibits osteogenic differentiation and stimulates osteoclast activity, ultimately leading to alveolar bone loss.⁵⁶ Tang et al³⁷ developed a Zn/Co BMOFs nano-platform that effectively scavenges excess ROS through a cascade of enzyme-mimetic antioxidant activities, thereby protecting hBMSCs and MC3T3-E1 cells from oxidative stress and promoting their differentiation toward an osteogenic phenotype. Animal studies further confirmed that Zn/Co BMOFs not only alleviate local inflammation and reduce osteoclast numbers but also enhance the regeneration of alveolar bone in critical-sized defects.

In another vitro study, Shu et al⁵⁷ developed a MOF-TCP composite scaffold by functionalizing β-TCP scaffolds with Zn/Co-BMOFs. The resulting scaffold not only exhibits excellent ROS-scavenging capacity and favourable biocompatibility, but also promotes osteogenic differentiation and chondrocyte maturation through the controlled release of active ions such as Zn²⁺ and Co²⁺ during its degradation. More importantly, this scaffold establishes a stable anti-inflammatory immune microenvironment during the repair process of the defect, demonstrating superior tissue integration and long-term therapeutic efficacy. Bai et al³⁸ reported a tumour-targeting nanoreactor (NMC/NTC) based on Zn/Co BMOFs, which can simultaneously trigger multiple synergistic therapeutic mechanisms within the tumour microenvironment in animals models. Specifically, Co²⁺ catalyses the decomposition of H₂O₂ to generate O₂, thereby enhancing the production of singlet oxygen and improving the efficiency of photodynamic therapy. Furthermore, after heat treatment, Co²⁺ imparts magnetic properties to the MOFs, enabling the nanoparticles to accumulate at the tumour site under the guidance of an external magnetic field, thereby enhancing targeting precision. Additionally, Zn²⁺ exhibits inherent immunomodulatory effects and, in combination with metformin and 1-MT, acts synergistically to reverse the immunosuppressive tumour microenvironment.

In summary, Zn/Co BMOFs represent a multifunctional and intelligent nanoplatform that integrates drug delivery, catalytic oxygen generation, magnetic targeting, and synergistic therapy into a single system, demonstrating considerable promise for tumor treatment applications.

The Cu/Zn BMOFs system

The Cu/Zn BMOFs system has emerged as a versatile platform with significant potential in both antibacterial and anticancer therapeutics.^58,59 To address the limitations of conventional antibacterial chemodynamic therapy (aCDT), such as incomplete sterilization and secondary infections due to the short lifespan of ROS. Peng et al³⁹ developed a domino microreactor (BMOFs-DMR) by integrating Cu/Zn-BMOFs with GOx. This system synergizes aCDT with starvation therapy: GOx catalyses glucose to generate H₂O₂, while Cu²⁺ triggers a cascade reaction that produces highly toxic •OH, concurrently depleting bacterial energy stores and GSH. This results in a multistage amplified antibacterial effect. Furthermore, the system promotes epithelialization and neovascularization, significantly accelerating the regeneration of infected skin wounds, thereby representing an ideal antibacterial platform that combines potent bactericidal activity with tissue repair functionality.

In the context of cancer therapy, Cu/Zn BMOFs also demonstrate multimodal, synergistic efficacy.⁶⁰ Although conventional chemotherapy exhibits potent cytotoxicity, it is often associated with severe side effects, drug resistance, and metastatic risk. To overcome these challenges, Wang et al⁴⁰ reported a DNAzyme-encapsulated Cu/Zn BMOFs system that combines intracellular in situ drug synthesis with gene therapy for precise cancer cell targeting. After being internalized by cancer cells, the BMOFs degrade under the acidic lysosomal environment, releasing Cu⁺, Zn²⁺, and DNAzymes. The Cu⁺ ions catalyse a bioorthogonal copper-catalysed azide–alkyne cycloaddition (CuAAC) reaction to synthesize anticancer drugs intracellularly, while Zn²⁺ activates DNAzymes to cleave metastasis-related gene substrates, enabling simultaneous gene silencing therapy. Since the anticancer drug is synthesized directly within tumour cells, this approach minimizes damage to normal tissues while effectively inhibiting tumour proliferation and metastasis, offering a promising strategy for precision oncology.

The Fe/Ni BMOFs system

In recent years, Fe/Ni BMOFs have demonstrated significant potential in the fields of biosensing and nanozymes due to their unique structural characteristics and exceptional catalytic performance.⁴¹ The core advantage lies in the synergistic effects between the two metal centres: the Fenton reaction activity of Fe and the electron-modulating capability of Ni complement each other, significantly accelerating electron transfer and the generation of •OH radicals, thereby enhancing the peroxidase-like activity of the material.61, 62, 63 This cooperative catalytic mechanism involving electron transfer and radical generation effectively improves the sensitivity and selectivity of Fe/Ni BMOFs in electrochemical signal amplification and target detection.⁶⁴

In terms of biosensing applications, Fe/Ni BMOFs have been successfully employed in platforms for detecting AFP-L3, a biomarker for hepatocellular carcinoma (HCC). By providing active sites and enhancing electron transfer efficiency, in combination with AgNPs as signal tags and an ‘off-on’ switching strategy, a detection limit as low as 69 pg/mL was achieved, showing promise for early diagnosis and prediction of HCC.⁶⁵ Additionally, Fe/Ni BMOFs exhibit excellent performance in glucose detection through coupling with GOx, enabling ultrasensitive detection of H₂O₂ and demonstrating their superiority as integrated nanozymes.⁴²

With ongoing advancements in structural modulation strategies – such as optimized synthesis processes, adjustment of metal ratios, and the incorporation of conductive substrates – the stability, conductivity, and catalytic performance of Fe/Ni BMOFs are expected to be further improved.

In summary, Cu/Fe BMOFs generate ROS via the Fenton reaction, demonstrating significant antibacterial and antitumor effects, particularly suited to pathological contexts requiring ROS‑induced cell death, such as cancer therapy. In contrast, Zn/Mg and Zn/Co BMOFs modulate ROS levels through distinct mechanisms: the former shows considerable advantages in bone regeneration, while the latter mitigates excessive ROS to reduce inflammation and promote bone repair. Although each metal system operates through different antioxidant mechanisms, they collectively offer versatile therapeutic options – especially in antibacterial, anti‑inflammatory, osteogenic, and antitumor applications – highlighting substantial potential for clinical use. Therefore, the choice of metal species should be tailored to the specific pathological requirements, thereby advancing the clinical translation of BMOFs in oral medicine.

BMOFs for oral application

Oral biofilm infections

The oral cavity constitutes a complex ecosystem harbouring diverse microbial communities (Figure 3). Dysbiosis within this ecosystem can lead to highly pathogen-specific infectious diseases, among which dental caries represents the most prevalent bacterial infection.⁶⁶ Streptococcus mutans (S. mutans) is regarded as an indispensable pathogen in caries development due to its specific cariogenic traits, including acid production, acid tolerance, and synthesis of extracellular polymeric substances (EPS).^67,68 This bacterium utilizes glucosyltransferases to produce EPS scaffolds that promote plaque biofilm formation, while its acidogenic metabolism of dietary carbohydrates lowers the local pH, leading to demineralization of dental hard tissues. Consequently, strategies aimed at inhibiting the viability of S. mutans and disrupting its biofilm formation are crucial for caries prevention and treatment.

Fig. 3.

BMOFs for oral application.

As a representative example, Wang et al⁶⁹ developed multilayer nanoparticles, designated O₂-Cu/ZIF-8@Ce6/ZIF-8@HA (OCZCH), specifically engineered to exploit the acidic and anaerobic oral microenvironment. In preclinical models, this system effectively eradicated Streptococcus mutans and its biofilms without relying on conventional antibiotics. The structure incorporates ZIF-8 frameworks formed by the coordination of Zn²⁺ with 2-methylimidazole. These coordination bonds are acid-labile, disintegrating at approximately pH 6.5 to enable an acidic-responsive release. Furthermore, the incorporated Cu⁺/Cu²⁺ species exhibit reversible oxygen coordination, which doubles the oxygen adsorption capacity of Cu/ZIF-8. The released Cu²⁺ ions exert auxiliary antibacterial effects by disrupting bacterial membrane potential and interfering with the respiratory chain. The synergistic combination of these mechanisms enables highly efficient eradication of S. mutans biofilms in the hypoxic and acidic oral environment. While direct experimental evidence for the in vivo anticaries efficacy of this BMOFs is currently lacking, both the acid-responsive release mechanism of Zn²⁺ and the antimicrobial action of Cu²⁺ are well-established mechanisms that have been demonstrated in extensive studies on single-metal MOFs structures.^70,71 Research on BMOFs that exploits the synergistic effect of these two ions has already been reported in other antimicrobial disease models, beyond dental caries, thus warranting further investigation.⁷²

Beyond antibacterial applications for caries control, BMOFs also show promise in caries risk assessment. For instance, Wu⁷³ and colleagues collected 287 paediatric saliva samples and, utilizing ZIF‑8 modified nanoporous membranes, determined the Michaelis constant (Km) of urease in each sample. This approach provides a novel tool for the early screening of dental caries. In this system, Zn²⁺ bridged by 2-methylimidazole forms sub-nanometre pores (0.34 nm) that permit selective permeation of OH^- ions, thereby amplifying the urease signal. The Au cathode, which also enabled the electrodeposition of ZIF-8, acted synergistically with it to convert urease activity into a readable electrical signal within a 5-minute timeframe. Although Au has been widely incorporated into various bimetallic systems for its anti-inflammatory and antibacterial functions, this nanoporous membrane design provides new insights that broaden its application scope and offer novel perspectives for caries detection.

Peri-implantitis is a microbial infectious disease occurring at implant sites, primarily caused by bacterial contamination and poor oral hygiene. Non-surgical treatment for peri-implant infections mainly involves mechanical debridement and adjuvant therapies, aimed at removing dental plaque. However, mechanical debridement may compromise the surface properties of dental implants, and the use of antibiotics may contribute to bacterial resistance. Therefore, current research focuses on enhancing the antibacterial performance of dental implants through various approaches, including the application of novel biomaterials and surface modification strategies.⁷⁴

Surface modification strategies have been extensively investigated, with some researchers exploring the application of MOFs within preclinical models. For instance, Choi et al⁷⁵ coated titanium implants with a near-infrared (NIR)-responsive multifunctional nanocomposite, Au@ZIF-8, to create an antibacterial coating. Specifically, in vitro cellular experiments have demonstrated that ZIF-8, through the release of Zn²⁺, upregulates the expression of genes associated with osteogenesis, resulting in a subsequent promotion of calcium deposition and bone tissue regeneration. Meanwhile, under NIR irradiation, Au nanoparticles generate a photothermal effect that confers bactericidal capability. The combination of these effects enables simultaneous antibacterial activity, photothermal therapy, and osteogenic function.

Similarly, Ag⁺ exhibits properties analogous to Au. Yang et al⁷⁶ fabricated a porous ZIF-8@Ag MOF in situ on sulfonated polyetheretherketone (PEEK). Ag⁺ ions were electrostatically adsorbed within the ZIF-8 pores, synergizing with Zn²⁺ to enhance antibacterial efficacy.

In a more advanced approach, Li et al⁷⁷ developed a BMOFs coating with pro-angiogenic capability. This system was fabricated by encapsulating CaO₂@ZIF-67 core-shell particles within a pH-responsive hyaluronic acid-adipic acid dihydrazide (HA-ADH) matrix, thereby integrating antibacterial, osteogenic, and angiogenic functions within a single platform. Under acidic conditions, CaO₂ reacts with water to release H₂O₂, which is subsequently catalysed by Co²⁺ to generate a substantial amount of hydroxyl radicals. These highly reactive •OH species then exert antibacterial effects by attacking bacterial membrane lipids, proteins, and DNA. Under neutral conditions, the Co²⁺ released from ZIF-67 acts as a signal transducer and activator, synergising with Ca²⁺ to promote osteogenesis. Evidence from RT-qPCR analyses indicates that Co²⁺, by stabilizing hypoxia-inducible factor (HIF), significantly upregulates the expression of key pro-angiogenic factors such as FGFR, VEGF, and eNOS. Furthermore, in a rat animal model, the CaO₂@ZIF-67-HA-ADH composite demonstrated the highest bactericidal rate and the most favourable osteogenic efficacy. Both Micro‑CT analysis and histological staining consistently supported these findings. Collectively, these results lay the groundwork for subsequent clinical validation and translation.

Currently, while preliminary studies have demonstrated the potential of BMOFs to inhibit dental caries and modify implant surfaces for antimicrobial purposes under oral microenvironment conditions, the existing evidence remains confined mainly to in vitro cellular experiments and small animal models. Research has yet to advance to extensive animal studies or clinical trials. Key limitations include an unclear translational relationship between clinically relevant doses and exposure durations, a lack of data on long-term efficacy and potential antimicrobial resistance, as well as insufficient systematic evaluation of material stability and activity retention within the complex oral environment, which involves challenges such as salivary clearance and enzymatic degradation.

Oral inflammatory diseases

Oral inflammatory diseases encompass a spectrum of conditions, including periodontitis, oral ulcers, and peri-implantitis. As peri-implantitis has been discussed in the preceding section, it will not be elaborated further here. This section will focus specifically on periodontitis.

Periodontitis is a chronic inflammatory disease whose pathogenesis is closely associated with local immune dysregulation and inflammation-induced oxidative stress.⁷⁸ ROS are a group of highly reactive oxygen-derived chemical entities, including H₂O₂, superoxide anion, singlet oxygen, and hydroxyl radical. They play a crucial role in the host’s innate immune defense.^79,80 However, a pathological surge in ROS levels can trigger oxidative stress, leading to damage to cellular lipids, proteins, and nucleic acids, thereby exacerbating inflammation and tissue destruction through multiple pathways. In chronic inflammatory oral conditions, dysregulated immune responses result in excessive ROS production, which in turn amplifies inflammatory processes and promotes tissue damage.⁸¹

In light of this pathological feature, Tang et al³⁷ developed a Zn/Co BMOFs. Although the Zn²⁺ released from ZIF-8 promotes osteogenesis, it lacks ROS scavenging capability. To address this limitation, cobalt ions were incorporated. Therefore, the incorporation of Co ions introduces a Co²⁺/Co³⁺ redox couple capable of valence transition, which mimics the activities of native antioxidant enzymes, specifically SOD and CAT. This enzyme-mimetic functionality enables effective ROS scavenging, significantly alleviating local periodontal inflammation and inhibiting bone resorption. In vitro experiments demonstrated that this material markedly reduced intracellular ROS levels under H₂O₂ stimulation, thereby promoting the survival of BMSCs and enhancing their osteogenic differentiation. These beneficial effects were further corroborated by in vivo studies using animal models. A rat model of periodontitis was established by ligating an orthodontic wire around the maxillary first molar for 6 weeks. Multiple datasets confirmed that the Zn/Co BMOFs group exhibited significant reversal of alveolar bone resorption and soft tissue destruction. Moreover, at effective treatment doses, no considerable cytotoxicity, haemolysis, organ damage, or metal accumulation was observed, indicating favourable in vitro and in vivo safety profiles.

A similar rationale was applied in the work by Li et al,⁸² who developed cerium-doped ZIF-8. Through its unique Ce³⁺/Ce⁴⁺ redox cycling, cerium mimics the activities of superoxide dismutase and catalase, actively scavenging the excess ROS generated by Zn²⁺ and the inflammatory microenvironment, thereby enhancing biosafety. By doping with cerium, ZIF-8 acquires dual functionalities, including antibacterial and anti-inflammatory effects, while demonstrating improved biocompatibility. Both CCK-8 assays and live/dead staining confirmed that at a cerium doping ratio of 10% and a concentration of 30 mg/mL, the material exhibits favourable safety. Notably, future studies should include animal model experiments to corroborate these in vitro findings.

The studies above primarily focus on addressing the inherent limitations of ZIF-8 as a therapeutic agent for periodontitis by incorporating other metal ions to scavenge ROS and mitigate local inflammatory responses, thereby achieving therapeutic effects. However, it is noteworthy that periodontitis is an infectious disease initiated by subgingival plaque biofilms. In the early inflammatory stages, the potent antimicrobial properties of ROS in controlling microbial colonization should not be overlooked. This mechanistic insight has spurred the development of a series of antibacterial materials designed to leverage this endogenous defense mechanism.

Wang et al⁸³ and colleagues successfully synthesized Cu-doped ZIF-8 via a solvothermal method, in which Cu²⁺ partially substitutes Zn²⁺ to form a Cu/Zn BMOFs. Within the MOFs structure, copper is embedded in the ZIF-8 lattice in the form of Cu⁺, forming low-coordination CuN₃ active sites that facilitate O₂ adsorption and electron transfer, thereby activating oxygen to generate ROS. The resulting ROS interacts with bacteria, inducing oxidative stress and membrane damage.

In a different approach, Zhang et al⁸⁴ constructed a novel nanozyme material, designated Cu(II)@ZIF-8 NPs, via a physical adsorption method. Studies revealed that, compared to conventional ZIF-8 nanomaterials, the incorporation of Cu²⁺ imparts dual enzyme-mimetic activities – specifically, oxidase-like and peroxidase-like functionalities. This enables the material not only to catalyse the depletion of intrinsic bacterial antioxidants but also to catalyse H₂O₂ further, generating highly reactive hydroxyl radicals, thereby conferring potent antibacterial efficacy. Additionally, Cu²⁺ can specifically bind to carboxyl and amino groups in the peptidoglycan of bacterial cell walls, facilitating the penetration of copper ions into bacteria and resulting in bacterial death. In summary, the two teams adopted distinct strategies for introducing Cu into the MOFs structure to synthesize BMOFs. Owing to the different synthesis approaches, the incorporated copper exists in different valence states, leading to fundamentally divergent antibacterial mechanisms.

In summary, the two research groups adopted distinct strategies to incorporate copper into the MOFs architecture, yielding BMOFs. Owing to differences in synthesis methods, the incorporated copper exists in different valence states, leading to divergent antibacterial mechanisms.

During the pathogenesis and progression of periodontitis, it is particularly crucial to develop an intelligent ROS-regulating system capable of responding to inflammatory conditions at different time points, thereby dynamically balancing antibacterial efficacy and inflammatory control to achieve optimal periodontal tissue regeneration. Currently, no BMOFs targeting this specific requirement have been constructed, highlighting a worthwhile direction for future research.

Furthermore, within the inflammatory microenvironment of periodontitis, excessive accumulation of ROS under oxidative stress can induce mitochondrial damage, further leading to the leakage of mitochondrial ROS (mtROS).⁸⁵ This burst of mtROS establishes a positive feedback loop that amplifies ROS production and exacerbates mitochondrial injury. Mitochondrial dysfunction, in turn, promotes further inflammation, creating a vicious cycle. In contrast to conventional ROS-scavenging approaches, Zhu et al⁸⁶ proposed a novel strategy aimed at controlling mitochondrial damage at its source to prevent the amplification of inflammation. They constructed a Mn/Ce BMOFs framework, in which Ce exerts its SOD-mimetic activity, while Mn exists in both tetravalent and divalent states. On one hand, Mn⁴⁺, present in the form of MnO₂, provides CAT-mimetic activity, thereby contributing to ROS scavenging. On the other hand, under the reductive microenvironment within cells, MnO₂ decomposes to release Mn²⁺. These ions act as signalling molecules that rapidly activate SIRT1-mediated deacetylation of FOXO3, promoting its nuclear translocation and upregulating BNIP3 expression. This process initiates mitophagy, which clears damaged mitochondria and terminates the mtROS-driven positive-feedback loop. Ultimately, this restores the redox-osteogenic balance in periodontal ligament cells and inhibits alveolar bone resorption. Therefore, controlling the burst of ROS at its source represents a more effective strategy for managing periodontitis. Subsequent systematic animal experiments were conducted to validate these findings. A periodontitis model was established in male Sprague-Dawley rats, followed by local injection of MnO₂@UiO-66(Ce) at different concentrations 7 days post-modelling. Continuous administration for 3 weeks revealed that a dose of 8 μg per injection site yielded optimal therapeutic efficacy. H&E staining of major organs showed no significant abnormalities. Furthermore, the material was metabolically cleared within 7 days, demonstrating favourable in vivo safety.

During an mtROS burst, not only is mitochondrial damage exacerbated, but pyroptosis – a type of programmed cell death – is also induced, playing a critical role in the pathogenesis and progression of periodontitis. Excessive mtROS accumulation promotes the dissociation of TXNIP, which directly binds to the NLRP3 inflammasome and activates Caspase-1. This enzyme cleaves GSDMD, leading to the formation of 20 to 22 nm transmembrane pores, ultimately resulting in cell swelling and rupture. In the periodontitis microenvironment, pyroptosis of cells such as periodontal epithelial cells and osteoblasts further releases IL-1β/IL-18, amplifying both ROS and inflammatory responses, which directly damage periodontal tissues and inhibit bone regeneration.

To address this challenge, Yang et al⁸⁷ designed an ATP-responsive Mg/Zn-MOF. Within the inflammatory periodontal microenvironment investigated in vitro studies, Zn²⁺ precisely recognizes ATP signals and chelates with phosphate groups/adenine nitrogen atoms of ATP, triggering MOFs degradation and the targeted release of Mg²⁺ and Zn²⁺ ions to suppress pyroptosis. Specifically, Zn²⁺ inhibits the non-canonical pyroptosis pathway mediated by the Caspase-11/GSDMD axis, thereby reducing cellular sensitivity to LPS. Meanwhile, Mg²⁺ blocks Ca²⁺ influx, preventing GSDMD-NT pore formation and inhibiting the canonical NLRP3/Caspase-1 pyroptosis pathway. Through this dual-ion synergy – Zn²⁺ targeting the non-canonical pathway and Mg²⁺ suppressing the canonical pathway – pyroptosis is comprehensively inhibited. A series of experiments, including Micro-CT, H&E staining, and immunofluorescence, confirmed that this BMOFs significantly ameliorated the destruction of periodontal tissues. Furthermore, its biosafety was comprehensively validated across multiple dimensions, including cytocompatibility, hemocompatibility, and in vivo metabolism and toxicity. On the one hand, Mg/Zn BMOFs at concentrations of 30 μg/mL and below showed no significant toxicity to either fibroblasts or osteoblasts. On the other hand, small animal imaging revealed that the liver primarily metabolises Mg/Zn BMOFs and can be cleared relatively rapidly in vivo – a finding further supported by H&E staining of major organ sections.

Currently, BMOFs have been extensively investigated in the context of periodontitis and related inflammatory conditions. Their proposed therapeutic mechanisms primarily focus on scavenging ROS, modulating mitochondrial function, and inhibiting pyroptosis; however, whether additional therapeutic targets exist requires further exploration. The vast majority of current research remains at the stage of in vitro cellular experiments and in vivo animal studies, for which relatively standardized validation protocols have been established. Nevertheless, translational progress has not yet been reported, and validation using relevant large-animal models is still lacking. Moreover, the unique environment of the periodontal pocket – subject to salivary flow, gingival crevicular fluid turnover, and masticatory mechanical stress – often results in a short drug half-life. Consequently, a key direction for future research is to develop strategies that maintain stable drug concentrations within the periodontal pocket while mitigating the effects of these factors.

In summary, the key experimental limitations are reflected in three main aspects. First, a clear translational relationship has not been established between the microgram-to-milligram dose ranges used in vitro and in animals and the clinically effective local concentration required within the periodontal pocket. Second, observation periods in existing animal studies are generally short, with most not exceeding 4 weeks, resulting in a lack of evaluation regarding long-term tissue integration, stability of bone regeneration, and potential delayed toxicity. Third, systematic studies are still lacking on the biodegradation behaviour, metabolic pathways, and possible chronic immune responses elicited by prolonged material retention within the complex inflammatory microenvironment. These gaps urgently require addressing through standardized large-animal studies to advance the clinical translation of BMOFs.

Oral cancer

Oral cancer encompasses a spectrum of malignancies affecting the oral cavity, including oral squamous cell carcinoma (OSCC), melanoma, among others. Current therapeutic strategies primarily involve a multimodal approach that combines surgery with radiotherapy and/or chemotherapy.⁸⁸ Of these, oral squamous cell carcinoma represents the predominant subtype, accounting for approximately 90% of all cases. Multiple factors, such as excessive alcohol consumption, tobacco use, viral infections, and genetic predisposition, influence tumour progression. However, the tumour microenvironment (TME) plays a crucial role in carcinogenesis, governing key processes such as tumour progression, metastasis, and drug resistance. The TME is highly complex and characterized by various microenvironmental features, such as oxidative stress, acidosis, hypoxia, and intricate cell-cell interactions. Consequently, combination therapies targeting specific aspects of the TME hold considerable promise for achieving improved therapeutic outcomes.^89,90

The team led by Tang et al⁹¹ developed an intelligent nanodrug delivery system, termed CZGDH, based on a bimetallic framework that integrates chemotherapy, starvation therapy, and chemodynamic therapy through a cascade response to the TME. This system utilizes Cu/ZIF-8 as the core scaffold, co-loaded with GOx and DOx, and is surface-modified with HA. Leveraging the active targeting capability of HA, CZGDH specifically enters tumour cells. Within the acidic TME, the Zn–N coordination bonds in ZIF-8 – formed via self-assembly of Zn²⁺ and 2-methylimidazole – are cleaved, leading to framework disintegration and the release of the cargo (DOx, GOx, and Cu²⁺). DOX directly enters the nucleus to exert conventional chemotherapeutic effects, while GOx catalyses the oxidation of intracellular glucose, depleting energy substrates and generating H₂O₂ and gluconic acid, thereby inducing starvation therapy. Subsequently, the released Cu²⁺ first consumes intracellular GSH to form Cu⁺, which then triggers a Fenton-like reaction with H₂O₂ produced by GOx, generating highly toxic hydroxyl radicals. This process disrupts the cellular redox balance and induces cell death. Collectively, Zn2+ confers acid-responsive drug release, while Cu²⁺ depletes GSH, enabling chemodynamic therapy, which synergistically achieves precise drug release and potent antitumor efficacy. In vitro studies confirmed that 0.4 µg/mL represents the cytotoxic threshold. With an average particle size of 164.83 nm, the material meets the size criteria for passive tumour targeting. Subsequent H&E staining of tumour tissues in an established nude mouse model demonstrated that the CZGDH treatment group exhibited significant tumour cell necrosis without apparent systemic toxicity.

Numerous other drug delivery systems have been designed based on Zn²⁺-mediated acid-responsive mechanisms. For instance, Hao et al⁹² developed an intelligent delivery platform using ZIF-8 to load 5-fluorouracil (5-FU). Sequencing results confirmed that ZIF-8 amplifies the gene-silencing effects of 5-FU, thereby enhancing its antitumor activity against oral squamous cell carcinoma.

The team led by Gu et al⁹³ developed a nanoplatform based on Cu-ZIF-8 loaded with disulfiram (DSF) and modified with polyethylene glycol (PEG). Although similar to the CZGDH system designed by Tang’s group in its use of a Cu-ZIF-8 framework, the integrated antitumor mechanism involving Cu²⁺ differs significantly. Under the mildly acidic tumour microenvironment, the ZIF-8 framework disintegrates, releasing Cu²⁺ and DSF synchronously. These subsequently form a highly toxic copper chelate, Cu(DETC)₂, locally within tumour tissues. This chelate induces cancer cell apoptosis primarily by inhibiting proteasome activity, including blockade of the p97-NPL4 pathway. Three-dimensional tumour spheroid assays confirmed that under acidic conditions, at a drug concentration of 15 μg/mL, the intracellular ATP level decreased to 16.3%, accompanied by marked shrinkage of the spheroids. In contrast, the formulation exhibited negligible toxicity at physiological pH.

In addition to the aforementioned Cu-ZIF-8 bimetallic framework, the Mn²⁺/Zn²⁺ BMOFs constructed by Zhao et al⁹⁴ also demonstrates promising antitumor efficacy. Using ZIF-8 as an acid-responsive carrier, the system encapsulates the photosensitizer TCPP-Mn along with GOx, integrating photodynamic therapy (PDT), Zn²⁺-overloading treatment, and immunotherapy to enhance antitumor outcomes synergistically. In this composite, Mn²⁺ is derived from TCPP-Mn. Under 660 nm laser irradiation, Mn²⁺ generates singlet O₂, enabling its application in PDT. Furthermore, Mn²⁺ exhibits dual functionality by simultaneously generating oxygen and ROS. It catalyses the conversion of H₂O₂ – produced via glucose oxidation catalysed by GOx – into O₂, thereby alleviating tumour hypoxia and subsequently enhancing the efficacy of PDT. The other metal ion, Zn²⁺, not only contributes to metal-overloading therapy by disrupting mitochondrial membrane potential and inducing ROS burst-mediated apoptosis, but also promotes immunogenic cell death (ICD), leading to immune activation. Immunofluorescence analysis revealed the translocation of CRT from the intracellular compartment to the cell surface – a hallmark of ICD. This process facilitates dendritic cell phagocytosis and antigen presentation. The experiments above collectively demonstrate the activation of antitumor immune responses and suppression of tumour metastasis. Collectively, the aforementioned experiments demonstrate that this system can activate antitumor immunity and suppress tumour metastasis. The BMOFs, with an average particle size of approximately 100 nm, were administered intravenously at a dose of 5 mg/kg in a mouse subcutaneous tumour model. The group receiving laser irradiation plus the BMOFs treatment showed a significant reduction in tumour volume, with complete tumour regression observed in some mice. H&E staining of major organs and haemolysis assays confirmed the favourable biosafety profile of the formulation.

Magnetic resonance imaging (MRI) remains the preferred technique for visualizing anatomical details of tumours with high spatial resolution. Owing to its paramagnetic properties, Mn²⁺ serves as a T₁-weighted MRI contrast agent. The team led by Zhang et al⁹⁵ developed FA-conjugated PEG-modified manganese-doped ZIF-8 nanoparticles loaded with baicalin for MRI-guided targeted therapy in a murine melanoma model. Mn²⁺, with its high r1 relaxivity, significantly enhanced signal contrast in the tumour region. Moreover, compared to gadolinium-based agents, it offers improved safety by avoiding the risks of nephrogenic systemic fibrosis due to its non-radioactive nature, enabling real-time, non-invasive tumour localization and treatment monitoring. Additionally, the system synergistically promoted ferroptosis, as evidenced by increased lipid peroxidation and downregulation of key ferroptosis inhibitors (GPX4 and FTH1), thereby enhancing baicalin-induced ferroptotic cell death. Similarly, Pan et al⁹⁶ employed 5-fluorouracil-loaded Mn-ZIF-8 for in vivo MRI and drug delivery in glioma, following a comparable therapeutic rationale.

Regarding currently reported therapeutic BMOFs for oral cancer treatment, most utilize the acid-responsive mechanism of Zn²⁺ to trigger the degradation of ZIF-8, enabling the concurrent release of metal ions and loaded drugs. The incorporation of a second metal ion, such as Cu²⁺ or Mn²⁺, provides additional therapeutic modalities. However, existing research remains predominantly focused on the in vitro cellular level. Although preliminary efficacy has been validated in small animal xenograft models (eg, in mice), support from large-animal experiments and clinical translational studies is still lacking. Furthermore, critical gaps exist, including insufficient follow-up duration and a lack of comprehensive data on dose-response relationships, chronic toxicity, and long-term metal ion accumulation. Addressing these key issues is imperative through the conduct of large‑animal studies and long‑term toxicological investigations compliant with Good Laboratory Practice (GLP) standards, which is essential for enabling the genuine clinical translation of BMOFs.

Bone defects and osteoporosis

The repair of extensive bone defects caused by various factors such as trauma, orthopaedic surgery, tumour resection, and infection remains a significant challenge in clinical practice. Over the past few decades, bone tissue engineering has made tremendous progress.⁹⁷ There has been growing interest in the application of MOFs for bone tissue engineering in recent years. Owing to their high loading capacity and versatility in biomedical applications, BMOFs show great potential for widespread use in this field.

For instance, the research team led by Zou et al⁹⁸ employed a glutathione-mediated reduction synthesis method to prepare Cu(I)@ZIF-8, which was subsequently blended with PLGA and fabricated into a porous scaffold via 3D printing technology for the repair of infected bone defects. Zn²⁺ serves as an essential cofactor for ALP, directly enhancing its activity and facilitating phosphate deposition. Studies have demonstrated that it also activates osteogenesis-related signalling pathways, such as Runx2 and BMP-2, thereby accelerating callus formation, as evidence by in vitro studies. Within this bimetallic framework, the initially incorporated Cu²⁺ is reduced to Cu⁺ by glutathione. The Cu⁺ species exhibit superior antibacterial efficacy compared to Cu²⁺, largely attributable to their enhanced generation of ROS. Furthermore, Cu⁺ promotes the proliferation and differentiation of MSCs, stimulates ALP activity, and enhances calcium mineralization, collectively contributing to improved osteogenic performance. Subsequently established rat models demonstrated that the PLGA/Cu(I) @ZIF-8 scaffold group effectively suppressed in vivo infection, concurrently reducing both inflammatory responses and bacterial load.

Shu et al⁹⁹ developed a PCL/PLA/n-HA/Cu@ZIF-8 composite GBR membrane that exhibits integrated antibacterial, osteoconductive, and osteoinductive properties. The ZIF-8 group, in which Zn²⁺ serves as the primary active component, demonstrated significantly higher cellular activity compared to the blank control group. These findings suggest that Zn²⁺ promotes the proliferation of BMSCs, thereby facilitating osteogenesis, although the underlying mechanism warrants further investigation. Additionally, the copper ions loaded on this GBR membrane exist in the divalent state (Cu²⁺). This composite promotes osteogenesis through three distinct mechanisms: firstly, it upregulates the expression of osteogenesis-related genes such as RUNX2 and OCN, facilitating the formation of mineralized nodules; secondly, it interacts with angiogenic factors to enhance endothelial cell chemotaxis and induce microvascular formation, thereby supplying nutrients and oxygen to bone tissue; thirdly, it modulates the immune microenvironment by polarizing macrophages toward the anti-inflammatory M2 phenotype, reducing the expression of pro-inflammatory cytokines, and promoting the secretion of pro-osteogenic factors such as BMP-2 and VEGF, which indirectly enhance the osteogenic differentiation of BMSCs. In a rat periodontitis model, the Cu@ZIF-8 membrane demonstrated superior antibacterial and osteogenic capacity compared to commercially available GBR membranes, while exhibiting better tissue conformity for ease of clinical handling.

A hallmark of osteoporosis (OP) is the attenuated osteogenic differentiation and enhanced adipogenic differentiation of BMSCs, primarily attributable to the accumulation of ROS. In light of this, reducing ROS levels represents a promising therapeutic strategy for OP.¹⁰⁰ Mg is known to protect cell membranes from oxidative damage, motivating several studies to engineer Mg-doped ZIF structures to regulate BMSC osteogenic differentiation, thereby indirectly treating osteoporosis. For instance, Cai et al¹⁰¹ and colleagues employed a one-pot method to synthesize Mg-ZIF, which, due to its SOD-like and CAT-like enzymatic activities, effectively scavenges excess ROS in BMSCs. This intervention upregulates key genes involved in lipid metabolism (ELOVL2, FADS1, FADS2), thereby inhibiting adipogenic differentiation of BMSCs and indirectly promoting osteogenic commitment. Animal studies further confirmed that this material significantly enhances bone density, increases the number and thickness of trabeculae, reduces bone resorption, and demonstrates notable anti-osteoporotic effects.

In a separate study, Song et al¹⁰² utilized a one-pot aqueous co-precipitation method to load icariin (ICA) onto Mg-ZIF, achieving a system where Mg²⁺, ICA, and Zn²⁺ act synergistically in preclinical models to impart both osteogenic and antibacterial properties. Beyond synergizing with Zn²⁺ to disrupt bacterial membranes and exert antibacterial effects, energy-dispersive X-ray spectroscopy (EDS) confirmed that Mg²⁺ stimulates calcium and phosphate deposition, inducing a more abundant and uniform Ca/P mineralized layer in simulated body fluid. However, the study would benefit from further animal experiments to validate these findings.

Recent studies have demonstrated that Co²⁺ can promote chondrogenic differentiation, and the combined effect of Zn²⁺ and Co²⁺ has been validated in multiple studies. For instance, Qin et al¹⁰³ constructed a biomimetic bilayer hydrogel scaffold for the repair of osteochondral defects. First, in accordance with ISO 10993-4 standards, the scaffold demonstrated a haemolysis rate of less than 5%, meeting the requirement and indicating no haemolytic risk. Second, this scaffold enables in situ synthesis of MOFs via 3D printing technology, achieving spatiotemporally controlled release of metal ions, thereby guiding BMSCs to differentiate into both chondrocytes and osteoblasts and ultimately promoting osteochondral tissue regeneration. The upper layer consists of ZIF-67 loaded with Co²⁺ and synthesized in situ with sodium alginate and silk fibroin, while the lower layer is composed of ZIF-8 loaded with Zn²⁺, forming a spatially defined bilayered MOFs structure. By mimicking a hypoxic environment, Co²⁺ stabilizes HIF-1α and activates the Wnt/β-catenin pathway, upregulating the expression of SOX9 and ACAN to enhance chondrogenesis. In contrast, osteogenic differentiation is facilitated by Zn²⁺ through the activation of the MAPK and AKT signalling pathways, which increases the expression of osteogenic genes, such as RUNX2, Osterix, and OCN. Although this structure does not represent a BMOFs in the classical sense discussed in this review, it corroborates the potential of this bimetallic ion combination. Subsequent experiments in a rabbit knee critical-sized osteochondral defect model confirmed that the bilayer scaffold could simultaneously regenerate hyaline cartilage and subchondral bone within 12 weeks, demonstrating not only safety and efficacy but also superior repair outcomes compared to single-component MOFs scaffolds.

Similarly, Shu et al⁵⁷ developed a Zn/Co BMOFs through the coordination of Zn²⁺ and Co²⁺ with 2-methylimidazole (2-MIM), which was subsequently coated onto 3D-printed β-tricalcium phosphate scaffolds via in situ deposition for treating osteochondral defects caused by osteoarthritis. While no direct evidence indicates osteogenic effects of Co²⁺ alone, it stabilizes HIF-1α to simulate a hypoxic microenvironment and induces the expression of angiogenic factors such as VEGF. When released synergistically with Zn²⁺, it enhances the expression of osteogenic genes, including RUNX2 and OCN. Moreover, the osteogenic mechanism of Zn²⁺ was consistent across both studies. The research group also established a rabbit model of a critical-sized osteochondral defect in the knee. Micro-CT and histological analyses revealed that, compared to pure β-TCP scaffolds and blank controls, the functionalized β-TCP scaffold enabled simultaneous reconstruction of both hyaline cartilage and subchondral bone within 12 weeks, with superior regenerative outcomes.

Additionally, this bimetallic system has demonstrated osteogenic potential in a periodontitis model, where Co²⁺ indirectly promoted bone formation by scavenging ROS, reducing the expression of inflammatory factors such as IL-1β, and inhibiting osteoclast differentiation. These effects synergized with the Zn²⁺-mediated Wnt/β-catenin signalling pathway to enhance osteogenesis. In summary, Zn²⁺ serves as the primary osteogenic agent, while Co²⁺ plays a supportive role. The osteogenic potential of this bimetallic system is considerable and warrants further investigation to expand its applications in bone regeneration (Figure 4).

Fig. 4.

Applications of BMOFs in oral medicine. a, Schematic illustration of the fabrication process of DOX@Fe/CuTH HaMOF and its role as a reactive oxygen species (ROS) amplifier and Cu/Fe metabolism disruptor in synergistic ferroptosis/apoptosis-based antitumor therapy (Copyright©2022, Wiley-W.J. Xu).⁴⁶ b, schematic of the synthesis, mechanism, and application of Fe₃Ni-MOF/GOx (Copyright©2022, ACS-Z. Mu).⁶⁴ c, synthesis of Mg/Cu BMOFs coating and its effects on promoting osteogenic differentiation and enhancing angiogenesis in endothelial cells (Copyright©2024, ACS-K. Chen).³⁵ d, schematic diagram of the Zn/Co BMOFs for periodontitis treatment (Copyright©2025, Wiley-H. Tang).³⁷

Overall, the osteogenic effects exerted by ions within BMOFs structures can be attributed to two primary mechanisms. On one hand, specific ions possess inherent osteogenic and chondrogenic inductive capabilities. On the other hand, they indirectly promote bone formation by modulating inflammation, stimulating angiogenesis, or inhibiting osteoclast activity. Since many ions exhibit one or more of these functions, a key challenge in material design lies in balancing the loading ratios of different metal ions to maximize osteogenic performance while maintaining concentrations below toxic thresholds. Furthermore, achieving sustained release and ensuring that the long‑term degradation kinetics of osteogenic scaffolds align with the natural rhythm of bone regeneration remain significant hurdles for bimetallic systems in bone tissue engineering.

Although the osteogenic efficacy of BMOFs has been validated in rodent models, such as calvarial defect and critical-sized osteochondral defect models, their translation to large-animal studies and clinical application faces multiple challenges. These include scalable and reproducible synthesis, comprehensive long‑term biosafety evaluation, assessment of the maturity and mechanical competence of newly formed bone, and the lack of established regulatory standards.

Future research directions for BMOFs

BMOFs-based sensors for oral applications

BMOFs have demonstrated significant breakthroughs in electrochemical biosensing applications due to their exceptional structural and functional properties.^104,105 Their future development holds unique promise in the field of oral medical sensors, where their tunable metal synergistic effects and multifunctional characteristics offer innovative solutions for oral health monitoring, diagnosis, and treatment (Figure 5).

Fig. 5.

Future trends of BMOFs.

In the context of salivary biomarker detection, miniaturized BMOFs-based sensors enable the real-time monitoring of diabetes-related glucose and the stress biomarker cortisol, and can also be applied in early screening for oral cancer.^106,107 For periodontal health assessment, BMOFs electrochemical sensors allow highly sensitive detection of periodontitis biomarkers, while simultaneously supporting surface-enhanced Raman scattering (SERS) detection and photothermal antibacterial activity.

There has been growing research interest in wearable sensors recently, due to their distinct advantages, such as rapid and accurate detection.¹⁰⁸ They also demonstrate considerable promise for healthcare applications, particularly in the diagnosis and monitoring of diseases.¹⁰⁹ In wearable device applications, flexible BMOFs sensors can be integrated into smart occlusal splint systems for dynamic, multi-parameter oral monitoring, and strain sensors provide real-time feedback for orthodontic force adjustments.¹¹⁰ In theranostic applications, pH-responsive BMOFs enable both the detection of caries-related microorganisms and the on-demand release of therapeutic agents, such as fluoride ions. Additionally, BMOFs-modified implant coatings can simultaneously promote osseointegration and provide an infection warning.

Future development should focus on technical advances such as anti-fouling sensor surfaces, integration with artificial intelligence-assisted analytics, and exploration of seamless integration with denture materials. By aligning closely with clinical needs, BMOFs-based sensors are poised to facilitate practical applications in personalized oral health management.¹⁰⁹

BMOFs-mediated targeted therapy for oral cancer

BMOFs primarily accumulate in tumour cells via the enhanced permeability and retention (EPR) effect. However, their lack of specificity and tendency toward drug leakage during delivery can lead to damage in normal tissues.^111,112 Therefore, active targeting can be achieved by functionalizing the surface of BMOFs with ligands that exhibit high affinity for tumour cells, such as FA, HA, and aptamers, all of which have been successfully employed in reported studies. This strategy promotes rapid and substantial accumulation of BMOFs at the tumour site within a short period, allowing effective therapy with reduced drug dosage. Future efforts may focus on developing integrin receptor-targeted BMOFs delivery systems functionalized with targeting moieties, such as RGD peptides or anti-EGFR antibodies, thereby significantly enhancing drug enrichment within tumour tissues.¹¹³ A key research direction involves optimizing the coordination microenvironments in bimetallic systems such as Zn/Cu or Zr/Fe to achieve synergistic delivery of chemotherapeutic and targeted agents.

Furthermore, pH/GSH dual-responsive BMOFs – eg, Fe/Mn BMOFs designed for the acidic tumour microenvironment of oral cancer – offer multifunctional therapeutic capabilities. On one hand, they enhance the Fenton reaction to generate ROS efficiently, they deplete GSH specifically within the tumour microenvironment, effectively overcoming antioxidant defense mechanisms. Additionally, such platforms can enable controlled release of immune checkpoint inhibitors, synergizing with chemodynamic therapy with immunotherapy. This multi-mechanistic strategy presents a promising research direction for overcoming treatment resistance in oral cancer.

BMOFs for the restoration of dental hard tissues

The application of BMOFs in the restoration of dental hard tissues primarily relies on their biomimetic mineralization capacity and ability to carry bioactive molecules. However, due to the complexity of the oral environment, conventional BMOFs still face challenges related to mineralization efficiency and stability. To address this, BMOFs can be functionalized with tissue-specific affinity ligands, such as polyaspartic acid or silane coupling agents, to enhance their enrichment at demineralized enamel/dentin interfaces through active targeting. Looking forward, the construction of dual-functional BMOFs delivery systems capable of simultaneous biomimetic mineralization and antibacterial action represents a promising direction. For instance, bimetallic synergistic frameworks, such as Zn/Ca BMOFs or Sr/Mg BMOFs, can be designed to optimize the coordination microenvironment for the sustained release of calcium/phosphate ions and the synergistic delivery of antibacterial metal ions.^3,114 Moreover, pH/enzyme dual-responsive BMOFs tailored to the cariogenic microenvironment – such as chlorhexidine-loaded Zr/Ti BMOFs – offer multifaceted reparative functions: they enable acid-triggered rapid release of mineralizing ions to promote remineralization, while also degrading in response to bacterial proteases to release broad-spectrum antimicrobial agents, thereby achieving simultaneous regeneration of demineralized tissue and eradication of cariogenic biofilms. Additionally, such platforms can be designed for the controlled release of odontogenic growth factors to activate dental pulp stem cell differentiation and facilitate reparative dentin formation.¹¹⁵ This integrated strategy combining mineralization, antibacterial activity, and regeneration provides a novel approach for addressing complex dental hard tissue defects.

Biosafety, technical bottlenecks, and translation challenges of BMOFs

The translation of emerging experimental materials or methodologies from the laboratory to clinical practice entails a series of challenges – and, consequently, numerous opportunities for future technological advancement.

Biosafety

While BMOFs demonstrate considerable application potential, their diverse chemical compositions and tunable physicochemical properties also imply significant uncertainty regarding their biosafety. Acknowledging the limitations of existing data, this section systematically summarizes preliminary toxicity findings and focuses on the standardized evaluation pathways that must be followed before clinical translation. For instance, research by Wu et al⁵³ indicated that Cu-MOF-74 reduced cell viability to 60% at a concentration of 80 µg mL⁻¹. In contrast, the introduction of Mg²⁺ to form MgCu₃-MOF resulted in cell viability exceeding 90% at the same dose. The safe dose was elevated from 50 µg mL⁻¹ for the monometallic counterpart to over 200 µg mL⁻¹ for the bimetallic system. Inductively coupled plasma optical emission spectrometry (ICP-OES) analyses revealed that the 24-hour Cu²⁺ release decreased from approximately 6 ppm to below 2 ppm in the MgCu₃-MOF, a level lower than the acute toxicity threshold (2.2 ppm) for osteoblasts.

This phenomenon is also observed in Zn/Co bimetallic systems. When the Co²⁺ ratio is less than 25%, the resulting particles exhibit a size of approximately 300 nm. CCK-8 assays indicated no cytotoxicity toward MC3T3-E1 cells at a dose of 100 µg mL⁻¹. However, a further increase in the Co ratio, even at the same dose, led to pronounced cytotoxicity, highlighting the inherent toxicity of Co ions. The mechanism involves Co²⁺ entering cells via ZIP-8 and DMT1 co-transport channels, leading to significant mitochondrial accumulation. This subsequently triggers oxidative stress and apoptosis, resulting in a sharp decline in cell viability to approximately 65%. Furthermore, variations in the metal ratio also alter particle size, another factor influencing nanomaterial toxicity.^37,116 Generally, particles within the size range of 120 to 225 nm exhibit the lowest toxicity, whereas those smaller than 50 nm or larger than 500 nm tend to accumulate in the liver and spleen due to enhanced cellular uptake or physical deposition, respectively.⁵⁹

Furthermore, during in vivo degradation, metal ions serve as the primary degradation by-products. Key factors such as ion concentration, ion species, and release kinetics collectively influence their biosafety profile¹¹⁷ (Table 3).

Table 3.

Degradation of BMOFs.

Material composition	Degradation conditions	Degradation time	Degradation products	Reference
FeCuMOF@PEG	pH 5.5	24 h	Fe²⁺/Fe³⁺, Cu²⁺, terephthalic acid derivatives, and low-molecular-weight PEG, are processed through endogenous iron/copper metabolic pathways or eliminated via renal/biliary excretion, with no cumulative toxicity observed	44
DOX@Fe/CuTH	pH 5.5 and 10 mM GSH	within 24 h	free DOX, Cu⁺/Fe²⁺, thiol fragments, and GSSG, all of which can be eliminated via renal/biliary excretion within 48 h, with no risk of long-term accumulation	46
DEX@ZnMgMOF74	pH 7.4	Within 7 d	Mg², Zn²⁺, DHTA, DEX; organ accumulation assays were not performed	34
Poloxamer Nanoplatform containing Zn/Co-MOF	pH 7.4	within 72 h	Zn²⁺, Co²⁺, 2-methylimidazole; no signs of cumulative toxicity within 14 d	37
Zn/Co-MOF@β-TCP	pH 7.4	12 wk	Ca²⁺, PO₄³⁻, Zn²⁺, Co²⁺, 2-methylimidazole; no inflammation or metal accumulation, meeting the recovery cycle for osteochondral defects	57
PDA/GOD@Zn/Co-MOF	pH 5.0	within 24 h	Zn²⁺, Co²⁺, 2-methylimidazole, PDA, GOD; no signs of cumulative toxicity within 48 h	38
Cu/Zn-ZIF @GOx	pH ≤ 5.6	24 h	Zn²⁺, Cu²⁺, 2-methylimidazole, Gox; showing no detectable organ accumulation within 7 d	39
ICG@Cu/Zn-MOF @MnO₂	pH 5.5,GSH,H₂O₂	within 24 h	Cu²⁺, Zn²⁺, ICG; showing no detectable organ ac cumulation within 7 d	60
DNAzyme@ Cu/ZIF-8	pH 5.5	24 h	Zn²⁺, Cu²⁺, 2-methylimidazole, the active DNAzyme, and an anticancer resveratrol derivative; showing no detectable organ accumulation within 7 d	40

Compared to monometallic MOFs, BMOFs exhibit more tunable degradation rates. For instance, Shane et al⁴⁷ constructed Mg/Zn bimetallic organic frameworks with varying metal ratios, loaded with curcumin, and evaluated their release profiles in PBS. The study revealed that a higher proportion of Mg accelerated the rate of curcumin release. Structurally, the Mg/Zn MOFs demonstrated greater stability in PBS than pure Mg‑MOF‑74, while degrading slightly faster than pure Zn‑MOF‑74, thus exhibiting degradation kinetics intermediate between the two single‑metal counterparts. This approach enables the modulation of degradation behavior without altering the fundamental framework or synthesis protocol, thereby mitigating potential adverse effects from abrupt ion release.

Separately, Zhong’s⁴⁴ team developed polyethylene glycol‑modified Fe-Cu BMOFs nanospheres with a controlled particle size of approximately 130 nm. MTT assays indicated that after 24 h of treatment at 200 µg/mL, cell viability remained high across different cell lines: 91.2% for HepG2 hepatoma cells, 92.4% for L929 normal fibroblasts, and 87.8% for mouse H22 hepatoma cells. These findings underscore that the safe concentration range of such nanospheres may vary depending on the cell type.

Compared to their monometallic counterparts, bimetallic MOFs exhibit significantly enhanced biosafety by incorporating biocompatible inert metals such as Fe³⁺ and Zr⁴⁺ to dilute toxic active centres like Cu²⁺ and Mn²⁺. This metal substitution strategy effectively mitigates safety concerns associated with toxic ion release while preserving the structural integrity of the framework and maintaining therapeutic efficacy.¹¹⁸

In a study by Tian et al,³¹ MTT assays and live/dead fluorescence imaging showed that Fe‑Cu bimetallic MOFs at 50 μg/mL led to higher cell viability than monometallic MOFs. The incorporation of Fe reduces the local density of Cu²⁺, which not only decreases Cu²⁺ release but also preserves the electron transfer efficiency at the peroxidase‑like active sites. This results in reduced cytotoxicity and ensures an effective balance between toxicity and functionality.

From the perspective of animal safety, the bimetallic strategy can synergistically accelerate degradation and reduce the duration of in vivo accumulation. Experimental results showed that after a single intravenous injection of CuBTC at 20 mg·kg⁻¹, hepatic copper accumulation in mice reached 25 µg·g⁻¹ at 72 h, accompanied by a two-fold increase in ALT levels. In contrast, when a Cu/Zn BMOFs with an equimolar ratio of Zn doping was administered at the same dose, hepatic copper accumulation decreased to 15 µg·g⁻¹, ALT levels returned to normal, and hepatic TNF-α expression was downregulated by 58%.^54,36

In summary, BMOFs leverage metallic synergy to overcome the limitations of monometallic MOFs in degradation kinetics and toxicity. On the one hand, by leveraging differences in chemical stability between metal nodes, precise tunability of material degradation rates in physiological environments is achieved, thereby avoiding acute toxicity risks from the burst release of metal ions. On the other hand, the introduction of highly biocompatible inert metals as structural supports can effectively ‘dilute’ highly catalytically active but potentially toxic metal centres. This strategy widens the material’s safety window without compromising the framework’s integrity or therapeutic efficacy. Such an optimal balance between functionality and biosafety underscores the superior biocompatibility of BMOFs, thereby facilitating their clinical translation.

For the successful clinical translation of BMOFs, it is imperative to establish a comprehensive, systematic evaluation framework. This entails conducting thorough biological testing of BMOFs in accordance with the International Organization for Standardization (ISO 10993-4) series of standards for the biological evaluation of medical devices. Critical assessments should include in vitro cytotoxicity, systemic toxicity analysis, and genotoxicity screening. Building on this foundation, preclinical research on BMOFs must be further refined, with particular attention to the long-term accumulation of released metal ions and the metabolic products of organic ligands, alongside a systematic evaluation of their safety pharmacology.

The transition from fundamental BMOFs research to first-in-human (FIH) clinical trials requires adherence to a stepwise translational pathway. This pathway commences with the stringent standardized preparation and multidimensional characterization of BMOFs, addressing key issues such as nanoscale particle size distribution, crystal structure stability, and batch-to-batch consistency. Subsequently, in vitro cellular experiments are essential for evaluating the biocompatibility of BMOFs, with a focus on discerning the differential impacts of various metal node and organic ligand combinations on cellular behaviour. At the mechanistic investigation stage, an in-depth exploration of potential specific toxicity pathways triggered by BMOFs is necessary, particularly concerning the disruption of intracellular redox homeostasis by metal ions and organic fragments generated during degradation.

Following these studies, preliminary animal experiments should be conducted in small-animal models to verify good laboratory practice (GLP) chronic toxicity before advancing to large-animal models or implantation studies. Ultimately, an integrated preclinical study protocol for BMOFs must be implemented under quality management-compliant conditions. This protocol must fully consider the unique drug loading and release properties conferred by the nanoporous structure of BMOFs, as well as their structural stability and degradation kinetics across different physiological environments. Completion of this preclinical testing pathway will provide the scientific foundation necessary for dose design and safety monitoring in FIH trials, thereby propelling the substantive translation of these novel materials from laboratory research to clinical application.

Technical bottlenecks

The clinical translation of BMOFs is confronted with a series of interrelated technical and regulatory hurdles. A primary manufacturing bottleneck lies in achieving reproducibility and batch-to-batch consistency during scale-up. Significant variations between batches – in crystal morphology, particle size distribution, specific surface area, pore architecture, and metal-ligand stoichiometry – can directly undermine drug loading efficiency, release kinetics, and the predictability of final biological effects.119, 120, 121 From an economic perspective, the reliance on high-purity metal salts, functionalized organic ligands, and often meticulously controlled synthesis conditions results in production costs substantially exceeding those of conventional dental materials. Consequently, developing green, efficient, and low-cost synthetic strategies has emerged as a crucial research direction to enhance economic feasibility.

In the context of scale-up production, achieving batch-to-batch reproducibility for BMOFs hinges critically on factors such as material cost and purity. These factors are decisive not only for the structural integrity, drug loading, release profile, and subsequent biological performance of the material but also for the economic feasibility of its large-scale manufacturing.¹²² Among them, the metal-ion ratio is a key determinant of the framework’s stoichiometric stability. Even minor deviations in the metal-to-ligand ratio can alter the coordination geometry at the nodes, leading to reduced crystalline phase purity or crystal phase transformation.¹²³ Specific surface area and porosity are key metrics for evaluating the structural openness and guest molecule accessibility of MOFs. Their values are highly susceptible to variations in multiple synthesis conditions, including reaction temperature, solvent system, moisture content, and precursor purity.¹²⁴ Slight fluctuations in any of these parameters may result in partial pore blockage, accumulation of crystal defects, and ultimately, significant performance disparities across different batches.¹²⁵ Furthermore, during scale-up, the cost of high-purity metal salts and functionalized organic linkers substantially exceeds that of traditional dental biomaterials. This material cost factor may significantly impact the feasibility of large-scale production.

On the other hand, BMOFs as drug delivery systems must typically undergo clinically acceptable sterilization procedures, the impact of which on material structural stability and performance cannot be overlooked. Autoclaving (high-temperature, high-pressure sterilization) may lead to the cleavage or reorganization of metal–ligand bonds, potentially causing framework collapse, reduced pore volume, or a significant decrease in specific surface area.¹²⁶ While irradiation sterilization avoids high temperatures, it can induce free-radical reactions in ligands, alter the oxidation states of metal nodes, or even trigger decoordination, resulting in lattice distortion or local disorder in the material.¹²⁷ Although filtration sterilization is relatively mild, it may selectively remove smaller nanoparticles from BMOFs formulations, thereby altering the particle size distribution.¹²⁸ Furthermore, most sterilization protocols may modify the material’s surface chemistry, for example, by chemically altering surface carboxyl, hydroxyl, or metal groups. These changes can indirectly affect the binding capacity for drug molecules, drug loading stability, and release kinetics.^129,130

Before clinical translation, the intended use pathway for BMOFs must be clearly defined, as this determines the specific regulatory requirements. If BMOFs are employed as medical devices (eg, antibacterial coatings or scaffold materials), they must comply with standards such as ISO 10993 for biocompatibility testing, and provide sterilization validation and mechanical performance data. If BMOFs function as drugs by loading and releasing bioactive substances, they are likely to be regulated as pharmaceutical products. This would necessitate the submission of GLP toxicology data (including 28-day repeated dose, genotoxicity, and immunotoxicity studies), PK/PD models, CMC (Chemistry, Manufacturing, and Controls) documentation, and Phase I/II clinical trial data. In cases where BMOFs serve as combination products, integrating both drug-delivery and structural-support functions, data for both the device and the drug components must be submitted concurrently for review by the FDA’s Office of Combination Products (OCP).

From a translational science perspective, the biological evaluation and regulatory pathway for BMOFs remain inadequately defined. Primarily, their regulatory classification must be determined based on the specific application scenario and mechanism of action, potentially categorizing them as medical devices, pharmaceuticals, or combination products. This classification will directly dictate the scope of required preclinical and clinical investigations. Consequently, a corresponding regulatory testing framework must be systematically established. Beyond standard biocompatibility assessments, particular attention must be paid to key safety endpoints, including the impact of sterilization processes on material structural stability and functionality, as well as long-term chronic toxicity, genotoxicity, and immunogenicity.

Therefore, to advance the clinical translation of BMOFs, it is imperative to establish a comprehensive framework encompassing controllable material fabrication, acceptable material costs, assessment of sterilization compatibility, regulatory science classification, and systematic toxicological evaluation. This framework not only provides an essential pathway to address current technical bottlenecks but also forms the scientific foundation for meeting future regulatory requirements and ensuring the safety and efficacy of clinical applications.

Challenges in clinical translation

The clinical translation of BMOFs faces three major challenges. First, batch-to-batch variations during large-scale synthesis – particularly in terms of crystal morphology, particle size distribution, and porosity – can directly impact drug loading efficiency and release kinetics.^106,131,132 Second, the production cost of BMOFs remains substantially higher than that of conventional dental materials, largely due to the requirement for high-purity metal salts and functionalized organic ligands. Developing green, efficient, and low-cost synthesis strategies is therefore essential to enhance their economic feasibility.^133,134 Finally, there is a lack of consistent standards for the biological evaluation of BMOFs. Currently, there is a notable scarcity of long-term follow-up data to evaluate potential risks of systemic immunomodulatory effects. Thus, establishing a comprehensive and unified assessment framework is imperative for future clinical translation.^135,136

Conclusion

In summary, this review has comprehensively discussed the synthesis methods of BMOFs, strategies for bimetallic selection, and their clinical applications in dentistry. As an emerging class of nanomaterials, BMOFs demonstrate remarkable potential in areas such as oral tissue regeneration, antibacterial and anti-inflammatory therapies, owing to their highly tailorable structures, synergistic metal-ion effects, multifunctional integration capacity, and responsive release properties within the oral microenvironment. However, it should be noted that research on BMOFs remains largely confined to the laboratory stage, with most studies conducted in animal models, such as mice. Clinical trials have not yet been initiated. Significant research gaps still exist regarding the clinical application and translation of these findings. Future studies should prioritize systematic safety evaluations to facilitate breakthroughs in clinical translation, thereby further unlocking the considerable potential of BMOFs in modern dentistry.

Data availability

Data will be made available on request.

CRediT authorship contribution statement

Yuhan Yang: Writing – review & editing, Writing – original draft, Validation, Supervision, Conceptualization. Qi Zhao: Writing – original draft, Visualization, Validation, Project administration, Methodology, Investigation, Data curation, Conceptualization. Zhanhua Cao: Writing – original draft, Visualization, Validation, Methodology, Investigation, Data curation, Conceptualization. Lingao Zhu: Writing – original draft, Visualization, Validation, Methodology, Investigation, Data curation, Conceptualization. Bowei Wang: Writing – original draft, Visualization, Validation, Methodology, Investigation, Data curation, Conceptualization. Zhihui Liu: Writing – review & editing, Validation, Investigation, Conceptualization.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.