MOFs can be incorporated with other base materials via various technical strategies to construct composite materials, where typical technical approaches encompass surface coating, electrospinning, 3D printing, and so forth.

The preparation of MOF-integrated composites as surface coatings mainly adopts ex situ synthesis strategies such as immersion coating. Specifically, by immersing the substrate material in a MOF precursor solution, MOF materials are allowed to deposit on the surface of the substrate or host matrix, forming a uniform coating. Methyl vanillate@ZIF-8 (MV@ZIF-8) is immobilized onto titanium surfaces to form a coating, mediated by polydopamine (PDA) (Si et al., 2023). This coating can sustainably release Zn²⁺ and MV, exerting antibacterial effects by inducing oxidative damage to bacteria, while promoting the early osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) (enhancing alkaline phosphatase (ALP) expression and extracellular matrix mineralization). A bone microenvironment-responsive MOF coating is constructed on titanium surfaces. By releasing Ce³⁺ and Sr²⁺, it scavenges excessive ROS associated with osteoporosis (OP), restores mesenchymal stem cell (MSC) function, promotes new bone formation, and enhances implant-mediated fracture healing efficacy (Chen M. et al., 2022). ZIF-67 nanoparticles loaded with osteogenic growth peptide (OGP) are deposited as a coating on the TiO₂ nanotube (TNT) surfaces of titanium implants (Tao et al., 2023). This coating not only possesses antibacterial properties and osseointegration capability but also effectively alleviates inflammatory responses and promotes immunomodulation by modulating macrophage polarization (reducing the secretion of pro-inflammatory cytokines).

MOFs can also form biocompatible osteoinductive materials with other materials via electrospinning. The microscale or nanofibrous networks constructed by electrospinning can closely mimic the structure of the extracellular matrix (ECM). Ghasemi et al. prepared poly-3-hydroxybutyrate-zein/UiO-66 electrospun composite scaffolds (Ghasemi et al., 2025). Cell viability, proliferation, adhesion, ALP activity, and ECM mineralization of the scaffolds were notably augmented, accompanied by significant upregulation of COLΙ, RUNX2, and OCN genes in MG-63 cells cultured on the scaffold surfaces. In addition, a β-cyclodextrin (β-CDs)/Ni-based MOF (β-CDs/Ni-based MOF) fibrous meshwork with intrinsic biocompatibility and biodegradability was produced through a highly efficient, fast, and controllable electrospinning technique, standing as a novel material option for orthopaedic uses (Lin J. et al., 2023). The β-CDs/Ni-based MOF scaffolds possess superior porosity, which can enhance proliferation as well as nutrient and oxygen transport, thereby facilitating more tissue regeneration.

With the continuous maturation of technology, 3D scaffolds with artificially controllable microstructures provide a potential strategy for bone tissue regeneration. For example, different amounts of UiO-66 nanocrystals were loaded onto alkali-heat treated 3D-printed titanium scaffolds, among which 1/2UiO-66/AHT exhibited excellent performance in osteogenesis and angiogenesis induction, and promoted intercellular communication by enhancing the paracrine effect (Liu et al., 2023). Xiao and his team prepared a novel magnetic nanocomposite, namely polycaprolactone (PCL)/Fe₃O₄@ZIF-8, via 3D printing technology (Xiao et al., 2024). This composite enhanced the proliferation and adhesion of rat bone marrow-derived mesenchymal stem cells (BMSCs); elevated the expression levels of osteogenesis-associated genes and proteins; stimulated the osteogenic differentiation of BMSCs via activation of the Wnt/β-catenin signaling pathway; alleviated infectious complications; and accelerated new bone formation in the context of infectious bone defects.

MOFs can be classified according to their functional applications, with particular emphasis on their intended uses across various domains. For instance, the presence of unsaturated metal sites within MOFs enables them to function as Lewis acid sites, thereby facilitating a range of chemical reactions (Rojas-Buzo et al., 2021). Furthermore, the porous structure and large surface area of MOFs endow them with superior performance in sensing and imaging applications. Among the MOF family, materials with structures from the MIL series are utilized. In particular, the combination of MILs with fluorescence has been employed for the detection of intracellular ATP molecules (Yao et al., 2021). Building on prior research findings, CD4⁺ and CD8⁺ helper T cells are acknowledged to participate in wound healing, hence immunosensors may serve as tools for monitoring the wound healing process (Neto et al., 2020; Solaimuthu et al., 2020).

Beyond these applications, MOFs are also used as drug carriers and vascular implants. MOF, with their high loading capacity and targeting ability, can control drug release. This is attributed to their high specific surface area, tunable structure, modifiability, and biodegradability, which make them efficient drug carriers (Hamedi et al., 2022; Aghazadeh Asl et al., 2023). Meanwhile, MOFs also show great potential in therapeutic interventions for diseases. As an illustration, the employment of copper-based MOFs in antithrombotic coatings for cardiovascular implant devices has seen growing adoption over the past few years (Sheng et al., 2024). With Cu-BTC employed as a catalyst, studies have verified that s-nitrosocysteine within blood samples undergoes transformation into cysteine and nitric oxide in vitro (Tsikas, 2021). Similarly, s-nitrosoglutathione may also undergo catalysis by more complex Cu-MOFs (Thai et al., 2022). Due to the nitric oxide-releasing properties of MOF/polymer composites, they are expected to be the preferred materials for new types of implants.

The one-pot synthesis (solution precipitation) involves the co-mixing of precursors in a solvent followed by a simple precipitation reaction under stirring. ZIF-8 was synthesized by Beyer et al. through the mixing of 2-methylimidazole and a zinc salt solution at ambient temperature (Beyer et al., 2016). Huang et al. prepared Zn-based MOFs (MOCP) using Zn(NO₃)₂ and 1,4-benzenedicarboxylic acid (H₂BDC) as reactants in a DMF solution containing triethylamine (TEA) at room temperature (Huang et al., 2003). This straightforward mixing approach allows for the quick synthesis of thermally stable and highly porous MOCP nanocrystals at room temperature in large amounts. The resulting MOCP materials exhibit high purity and yields (>90%).

The advantages of this method include low cost, high yield, and easily achievable experimental conditions. ZIF-8 can be modified to have bioactivity greater than that of standalone zinc ions (Shyngys et al., 2021). During precipitation reactions, insulin or nonsteroidal anti-inflammatory drugs (NSAIDs) can be incorporated into the precursor mixture, leading to their robust immobilization and encapsulation within ZIF-8 (Ho et al., 2020; Rohra et al., 2022). Researchers can control this process effectively by adding reactants at any point during the reaction. Nevertheless, the MOFs produced through synthesis frequently have impurities, rendering this approach inappropriate for uses that demand high purity.

Creating materials through hydrothermal (solvothermal) synthesis is a technique that includes integrating solutions of metal ions and organic ligands as precursors in a closed system (e.g., a miniature autoclave), followed by heating in water or organic solvents to temperatures exceeding the solvent’s boiling point under autogenous pressure to facilitate the reaction. Chui et al. synthesized [Cu₃(TMA)₂(H₂O)₃]_n (denoted as HKUST-1) via a solvothermal reaction using Cu²⁺ and benzene-1,3,5-tricarboxylic acid (TMA) under elevated temperatures (Chui et al., 1999). HKUST-1 exhibits high porosity, enabling accessibility of its copper metal centers to solutes. This property allows Cu-BTC to catalyze the transformation of blood-borne S-nitrosothiols for sustained nitric oxide (NO) release (Yang L. et al., 2024). Li et al. employed Zn(NO₃)₂ and H₂BDC as reactants in DMF to synthesize MOF-303 through solvothermal synthesis. Experimental data indicate that MOFs prepared by this method demonstrate superior stability, enhanced porosity, exceptional gas adsorption performance, and higher crystallinity compared to those synthesized via the one-pot approach (Li et al., 1999). This improvement is primarily attributed to the elevated pressure under hydrothermal conditions, which increases precursor solubility and thereby accelerates reaction kinetics and crystal growth. However, this method suffers from high costs, harsh reaction conditions, significant energy consumption, and limited controllability—reactants must be added entirely at once, and prolonged reaction times (hours to days) result in low efficiency, making it unsuitable for rapid large-scale synthesis. Extended durations may also lead to crystal overgrowth or undesired byproduct formation.

Ultrasonic treatment utilizes the physical phenomena of cavitation effects, microjets, and localized environments with elevated temperature and pressure generated by ultrasound to enhance the mixing of dissolved reactants and crystal nucleation in solvents, thereby accelerating MOF synthesis. Yuan et al. first added specific quantities of iron (III) chloride, iron (II) chloride (at a Fe (III): Fe (II) molar ratio of 3:1), and 1 g of terephthalic acid (TPA) into a DMF solution (Yuan Z. et al., 2023). Following experimental design, cellulose fibers (CF) were incorporated at ratios of 20%, 30%, and 40% to prepare composite materials. The mixed solution was then subjected to ultrasonic treatment at 250 W power and 70 °C for 2 h. The interfacial regions between micro cavitation bubbles and the bulk solution exhibit extreme temperature/pressure changes and quick molecular dynamics (Qin et al., 2024), which facilitate the uniform growth of MIL-53(Fe) crystals on cellulose fiber surfaces and strengthen physical cross-linking and interactions involving hydrogen bonds between fibers and MOF crystals. This ultrasonic approach enables reactions that are challenging to achieve via conventional methods. For instance, reconstruction can be accomplished through mechanical disruption followed by re-ultrasonication.

Ultrasonic treatment constitutes an effective, environmentally sustainable, and streamlined methodology, particularly advantageous for laboratory-scale rapid synthesis and the fabrication of high-performance composite materials. Moreover, the acoustic cavitation effects facilitate specialized reactions that are not attainable through conventional techniques. Nevertheless, this approach encounters challenges related to equipment costs, material compatibility, process controllability, and scalability for industrial production.

The stepwise synthesis method involves sequentially constructing the metal node and organic ligand networks. This approach enables precise control over MOF structure and functionality through post-synthetic ion exchange for metal doping, without compromising crystallinity (Fan et al., 2023). Cheng et al. developed CoCu-based bimetallic MOF nanoboxes (CoCu-MOF NBs) via a sequential cation and ligand exchange strategy (Cheng et al., 2021). TA-Co NBs were created by using tannic acid to etch Co-based ZIF-67. Subsequent cationic exchange in Cu²⁺ solution partially replaced Co sites with Cu atoms, forming TA-CoCu NBs. In the end, the TA ligands in TA-CoCu NBs were substituted with 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP) ligands through ligand exchange, producing the final CoCu-MOF NBs.

The stepwise synthesis approach is highly effective in facilitating precise control over the composition and structure of materials, thereby substantially improving the catalytic performance of the oxygen evolution reaction. Nevertheless, the complexity of its synthetic procedures necessitates meticulous selection of ligand-metal combinations during exchange processes to avert framework collapse, consequently introducing an element of stochasticity (Fan et al., 2023). Furthermore, metal ions with diverse valences and ionic radii frequently adopt distinct coordination numbers and environments, thereby complicating the optimization of reaction conditions. Consequently, this often leads to reduced yields during the substitution of metal ions to replace the original metallic centers (Duan et al., 2020).

The electrochemical technique uses a metal electrode as the anode to emit metal ions through electrochemical oxidation or reduction occurring in a conductive medium, which subsequently interact with organic ligands in the solution to form monomers or various types of compounds and aggregates. This approach enables the construction of MOF thin films on electrode surfaces and has been widely adopted. Zhao et al. utilized a copper anode and 1,3,5-benzene tricarboxylic acid (BTC) as the ligand (Zhao T. et al., 2024). During the electrochemical reaction, the BTC ligands coordinated with copper ions to form an HKUST-1 thin film on the copper electrode. They observed that high-concentration electrolyte solutions provide abundant copper ions and BTC ligands, promoting rapid nucleation and growth of HKUST-1, resulting in large, uniformly distributed crystals. However, excessively high electrolyte concentrations may increase solution viscosity, hindering ion migration rates and compromising HKUST-1 growth quality. Similarly, high current densities accelerate electrochemical reaction rates and copper ion release, facilitating rapid nucleation and growth of HKUST-1 with uniform crystal distribution. Nevertheless, overly high current densities can elevate overpotential at the electrode surface, triggering side reactions that degrade the purity and performance of HKUST-1.

The electrochemical synthesis of MOFs offers advantages such as precise control over material composition and structure, mild reaction conditions, and enhanced electrical conductivity and electrochemical performance. Nonetheless, this technique is predominantly confined to the fabrication of thin films on conductive substrates, thereby limiting its widespread applicability.

The microwave-assisted method has been widely used for the rapid synthesis of MOFs under hydrothermal conditions. This approach employs microwave energy with frequencies spanning 300–300,000 MHz, offering an energy-saving and eco-friendly strategy for fabricating MOFs (Phan et al., 2023). Distinct from conventional heating techniques, microwave-assisted synthesis hinges on the interplay between mobile charges in polar solutions and microwave radiation to deliver the needed heat. It secures a consistent temperature increase throughout the reaction course and is not reliant on the demand for heat transfer within the reaction mixture, thereby accelerating crystal growth during MOF synthesis (Ren et al., 2022). The unique thermal properties of microwave-based approaches facilitate enhanced regulation of crystal size and structure, diminishing MOF particle dimensions down to the nanoscale range (Díaz de Greñu et al., 2021). This is crucial for the application of MOFs as drug delivery systems following different administration routes (Khan and Jhung, 2015). An appropriate particle size is a key factor ensuring the efficacy and safety of intravenous injection, as it is closely related to drug delivery efficiency, in vivo circulation time, organ/tissue accumulation, and targeting ability, among other aspects (Christodoulou et al., 2020; Wang A. et al., 2024). Similarly, when MOFs are administered via the pulmonary route, nanoparticles exhibit good colloidal stability, enabling localized drug delivery in the lungs without causing embolism due to excessively large particle sizes or rapid clearance due to excessively small ones (Fernández-Paz et al., 2020). However, it should be noted that MOFs require formulations with a size range of 1–5 μm. Particles within this range can penetrate deep into lung tissues through mechanisms such as sedimentation (in bronchioles) and Brownian motion (in alveoli); particles that are too large (>5 μm) tend to be retained in the trachea, while those that are too small (<1 μm) may be exhaled during respiration (Yu et al., 2025). Consequently, the microwave method has become an efficient way to synthesize MOFs.

While microwave-based approaches have established themselves as highly effective strategies for MOF synthesis, the microwave-assisted synthesis process is not devoid of constraints. The effectiveness of microwave heating is affected by the chosen materials, thereby necessitating meticulous regulation of synthesis parameters to optimize the characteristics of the end product. Moreover, microwave irradiation exhibits limitations such as challenges in reaction monitoring (Lozano Pérez et al., 2024).

The optimization of the physical properties of implants pertains to the structural customizability of MOF materials. This customization modifies interfacial properties to enhance variations in physical characteristics, including surface mechanical stress, growth interface topology, and surface charge, all of which are critically responsive to bone tissue interactions (Bolamperti et al., 2022; Wang L. et al., 2022). In recent years, the mechanisms of load transfer and the physicochemical properties of surfaces have been recognized as pivotal factors influencing interactions with diverse biomacromolecules and cells. These factors are crucial in attracting cells involved in osteogenesis at the implant interface and significantly impact their proliferation, differentiation, and mineralization processes (Wang L. et al., 2020; Shirazi et al., 2022). MOFs can be precisely engineered to replicate bone-like structures and elastic properties through strategic compositional modifications and optimized synthesis processes. These customized MOFs facilitate a more uniform distribution of mechanical loads at fracture sites, thereby preventing metallic implant components from assuming the role of primary load-bearing elements. This mechanical adaptation reduces the risk of stress-shielding, which can lead to bone atrophy and pathological remodeling (Luo et al., 2021; Raffa et al., 2021). Initially, Wang et al. applied a coating of Mg-MOF-74, a magnesium-based biocompatible compound, onto a 3D-printed porous Ti₆Al₄V substrate, subsequently encapsulating it with silk fibroin (Wang W. et al., 2022). Mechanical assessments revealed that the application of an Mg-MOF-74 layer to the porous titanium substrate significantly alleviated the stress-shielding effect attributed to stiffness mismatch, a prevalent problem in traditional titanium implants. This modification facilitated new bone formation within the titanium matrix, thereby improving osseointegration and achieving strong fracture fixation. Zhang and colleagues employed a biomimetic strategy, inspired by the microstructure of male eastern bluebird feathers, to develop a self-assembled MOF structure (Zhang et al., 2022a). This approach emulates the organic-inorganic interfacial configurations found in natural biomaterials, such as nacre, imparting the material with a distinctive non-iridescent structural coloration mechanism. The researchers augmented a supramolecular MOF that synergistically facilitates both antibacterial and osteogenic activities. Through the formation of Lewis acid-base adducts with 6-mercaptohexanoic acid nanoclusters and phytic acid (PA)-metal complexes, a multiscale supramolecular framework was established. This structure facilitates the recruitment of pre-osteoblasts and their subsequent differentiation into osteogenic cells. Phytic acid, abundant in phosphate groups, provides multiple sites for the chelation of Ca²⁺ ions, thereby expediting the process of biomineralization. Concurrently, coordinated metal ions such as Cu²⁺ and Zn²⁺ disrupt bacterial membrane integrity through sustained release, thereby inhibiting biofilm formation effectively (Zhang et al., 2023).

In physiological environments, metal ion release is the process where metal ions detach and are emitted from the crystalline frameworks of MOFs. Various metal ions, such as zinc ions (Zn²⁺), magnesium ions (Mg²⁺), strontium ions (Sr²⁺), iron ions (Fe³⁺), and titanium ions (Ti²⁺), have attracted research attention due to their demonstrated potential in promoting the osteogenic differentiation of BMSCs and regulating the expression of osteogenesis-related genes in eukaryotic cells (Chen et al., 2017; Chen J. et al., 2022; Kang et al., 2022; Li et al., 2024a; Li S. et al., 2024; Zheng et al., 2024). Researchers have synthesized numerous osteogenic MOFs by incorporating the aforementioned metal ions into their crystalline frameworks, consistently finding that the sustained release of metal ions is a critical determinant of their superior osteogenic performance (Luo et al., 2024). As an illustration, Wang et al. developed an innovative bone-targeting orthopedic implant made of a nutrient element coating and polyetheretherketone (PEEK) (Wang H. et al., 2021). Through the incorporation of ZnO and Sr(OH)₂ onto sulfonated PEEK surfaces (Zn&Sr-SPEEK), they demonstrated that the combined release of Zn²⁺ and Sr²⁺ from the coating eliminated harmful bacteria and greatly enhanced osteoblast activity in high glucose environments. Notably, the Zn&Sr-SPEEK implants demonstrated a strong capacity to restore high glucose-induced mitochondrial dyshomeostasis and dysfunction. This was accomplished by reducing the expression of the dynamin-related protein 1 gene, recovering mitochondrial membrane potential and clearing out ROS. As a result, osteoblast-mediated bone formation was significantly enhanced. Studies conducted on diabetic rat models with femoral/tibial defects at 4 and 8 weeks demonstrated that the nutrient element coating significantly enhanced bone restructuring and bone integration. In their study, Chen et al. developed zinc-based MOF films consisting of nanoscale and microscale ZIF-8 crystals on porous titanium surfaces through the application of hydrothermal and solvothermal processes (Chen et al., 2017). The ZIF-8 coatings promoted osteoblast proliferation and differentiation through sustained Zn²⁺ ion release. By upregulating the expression of osteogenesis-related genes like collagen type I (Col I), ALP, and bone morphogenetic protein (BMP), these ions facilitated the generation and calcification of the bone matrix. In a different study, Xiong and colleagues explored how low-intensity pulsed ultrasound (LIPUS) and Fe³⁺ together affect the proliferation and differentiation of osteoblasts (Xiong et al., 2024). Cell proliferation assays revealed that 400 μg/L Fe³⁺ exerted the strongest pro-osteogenic effect. ALP staining and mineralization assays demonstrated that LIPUS and Fe³⁺ synergistically enhanced osteoblast differentiation. Protein expression analyses further indicated that LIPUS and Fe³⁺ upregulated Wnt, β-catenin, and Runx2 signaling pathways, effectively promoting physiological bone regeneration and development.

Research has demonstrated that MOF can yield effective and sustained osteogenic outcomes through the continuous release of metal ions. This effect is primarily attributed to the increased ALP activity, enhanced mineralization of the extracellular matrix, and upregulation of osteogenic genes in MG63 cells. The release of metal ions serves as osteoinductive signals, while the simultaneous delivery of bisphosphonate linkers further augments bone mineralization (Li M. et al., 2022; Zhang et al., 2023). Moreover, Mg²⁺ ions generated via biodegradation have been observed to promote the osteogenic differentiation of MSCs by augmenting autophagic activity (Qi et al., 2021). Consequently, several hypotheses have been proposed concerning the mechanisms by which released metal ions facilitate osteogenesis. Some theories posit that these ions directly enhance the activity of key substances involved in osteogenic metabolism, whereas others propose that they stimulate gene expression to enhance the efficacy of bone repair.

It should also be noted that the controllable release of metal ions has been achieved through various strategies, with the core lying in leveraging the dynamic tunability and external stimulus responsiveness of MOF structures. Many MOFs undergo structural disintegration in acidic or alkaline environments, thereby releasing metal ions. Liu et al. discovered an easily designable resorbable guided bone regeneration membrane (PCL/DEX@Ca-Zol) based on drug-loaded metal-organic frameworks (Liu C. et al., 2024). Among them, the calcium ions, zoledronic acid, and dexamethasone embedded in the membrane can be specifically released in response at bone defect sites under acidic triggering, synergistically regulating the bone microenvironment (BME). Moreover, the strategy of using specific biomolecules (such as ATP) to trigger MOFs to release metal ions is also commonly employed in MOF design. Within the Mg/Zn metal-organic framework (MOF) synthesized by Yang et al., Zn²⁺ establishes a robust tetrahedral coordination complex via the nitrogen atoms in 2-methylimidazole (Xu Y. et al., 2024). Nevertheless, the adenine nitrogen moieties and phosphate groups of ATP are capable of forming chelates with zinc ions, and ATP exhibits a higher affinity for Zn²⁺ than 2-methylimidazole does. Within the periodontitis-specific inflammatory microenvironment marked by high ATP levels, this framework undergoes a response to ATP, facilitating the selective release of Mg²⁺ and Zn²⁺ at the inflammatory locus. Photoresponsive MOFs are also commonly used. For instance, RuFe-MOF undergoes structural changes under X-ray irradiation, releasing metal ions and generating ROS, which is applied in the synergistic radiotherapy and photodynamic therapy of tumors (Liu A. et al., 2025).

Thanks to their extensive surface area and significant porosity, MOFs are ideal for drug delivery (Figure 5). Therapeutic agents may be incorporated into MOFs via adsorption, encapsulation, non-covalent interactions, and covalent bonding. They enable effective delivery of short half-life pharmaceuticals, thereby enhancing treatment effectiveness. By customizing MOFs, they can display unique drug delivery traits like stimuli responsiveness and targeting, which allows for precise detection of pathological tissues (He et al., 2021). Osteoinductive agents encapsulated in MOFs effectively promote osteoblast differentiation and bone tissue regeneration through sustained release in physiological environments. At the same time, a strong blood supply provides nutrients and essential growth factors to osteoblasts, supporting synchronized and dynamic bone-forming activities in the bone microenvironment. In situations like inflammation, infection, or tumors, angiogenesis in specific areas is reduced, making it necessary to regulate externally by releasing pro-angiogenic agents. MOFs, with their extensive specific surface area, serve as excellent carriers for osteoinductive and angiogenic agents, where the drugs released effectively stimulate and hasten bone growth.

Under pathological conditions, elevated ROS levels induce substantial oxidative stress on bone tissue. This excessive ROS presence suppresses osteoblast activity while facilitating osteoclast formation, thereby disrupting the equilibrium of bone tissue. Such disruptions exacerbate local inflammation, accelerate bone resorption, and hinder bone regeneration (Tao et al., 2020; Yu et al., 2020). Consequently, the preservation of bone homeostasis is critically dependent on antioxidant activity. Strategies for scavenging exogenous ROS typically involve the neutralization of ROS through antioxidant agents, as well as their catalytic elimination via enzymatic or non-enzymatic pathways (Wang L. Y. et al., 2021; Kim and Kim, 2022).

MOFs are capable of delivering antioxidant agents and include metal atomic sites that can act catalytically. Different types of catalytic nanozymes have been designed, including those that act like catalase, superoxide dismutase, and glutathione peroxidase. Due to their adjustable active sites, structural variety, and outstanding biocompatibility, MOF-based nanozymes have wide-ranging potential applications in biomedicine and other fields (Xu Z. et al., 2024).

MOF-Fe is characterized by its unique unsaturated metal centers (UMCs). As a particle containing iron, it demonstrates properties similar to those of Fe₃O₄ and Fe₂O₃ particles. This distinctive characteristic imparts MOF-Fe with peroxidase-like activity, thereby positioning it as a potential catalyst (Cheng et al., 2023). Through the catalytic decomposition of hydrogen peroxide (H₂O₂), MOF-Fe effectively emulates the function of natural peroxidases. As a result, MOF-Fe holds significant potential for diverse applications as a peroxidase mimic (Thakur et al., 2021). In further investigations into the ROS-scavenging capacity of metal-organic framework iron (MOF-Fe), Xue et al. observed that experimental groups treated with MOF-Fe exhibited efficient scavenging of hydrogen peroxide, a component of ROS (Xue et al., 2024). The study further revealed that increasing concentrations of MOF particles were associated with a reduction in free radical levels. This conclusion was corroborated by DPPH radical scavenging assays, which demonstrated enhanced neutralization of DPPH radicals at higher concentrations of MOF particles. Notably, MOF-Fe particles were found to activate the bone morphogenetic protein (BMP) pathway by suppressing transferrin receptor 2 (TfR2), indicating significant potential for promoting bone formation.

Besides Fe-MOFs, various MOF-based nanozymes have been used for antioxidant purposes in bone tissue. Shu et al. developed Zn/Co-MOF-modified β-tricalcium phosphate (β-TCP) scaffolds to repair osteochondral defects. Shu and colleagues created β-tricalcium phosphate scaffolds modified with Zn/Co-MOF to mend osteochondral defects (Shu et al., 2023). Adjusting the concentration of the Zn/Co-MOF reactant solution allowed the MOF-TCP scaffolds to exhibit a broad spectrum of ROS scavenging properties and high biocompatibility. Remarkably, the MOF-TCP scaffolds advanced the osteogenic differentiation of BMSCs and the maturation of chondrocytes, while protecting them from oxidative stress by removing external ROS and supporting an anti-inflammatory microenvironment.

Simultaneously, Tan and colleagues engineered CaCO₃@ZIF@Mo-TA, a compound exhibiting antioxidant properties, by employing ion-exchange and self-assembly techniques to mitigate oxidative stress in compromised cartilage (Tan et al., 2025). The pH-responsive microenvironment facilitates the degradation of calcium carbonate on the ZIF@Mo-TA surface, leading to the release of calcium ions that contribute to the repair and regeneration of bone tissue associated with arthritis. Experimental data indicate that the porous internal structure of ZIF@Mo-TA, characterized by its numerous active sites, substantially reduces the expression and accumulation of intracellular ROS. Moreover, it promotes the release of anti-inflammatory agents, collaboratively modulating intracellular oxidative stress levels and establishing a supportive immune microenvironment conducive to joint healing.

In another study, Liu et al. designed two cerium-based metal-organic frameworks with monovalent properties (Ce-MOFs): Ce (III)-BTC and Ce (IV)-BTC, for scavenging superoxide radicals (O₂·^-) and protection against ionizing radiation (Liu et al., 2022d). Both Ce-MOFs selectively reduce O₂·^-, serving as excellent superoxide dismutase (SOD) mimics. Similar to natural SOD and ceria nanozymes, the SOD-like catalytic mechanism of Ce-MOFs involves the redox cycling between Ce (IV) and Ce (III). Experiments conducted both in vitro and in vivo confirmed that the Ce (IV)-BTC nanozyme is effective at removing ROS.

Under physiological conditions, the osseous microenvironment sustains moderate levels of ROS. Pathological stimuli, such as infections and toxins, can exacerbate oxidative stress within bone tissue, leading to a deleterious cycle. The effective scavenging of excessive ROS can mitigate inflammatory responses and facilitate the repair of bone tissue. However, the overall efficacy of these interventions is limited, making them predominantly applicable as preventive measures in related research studies.

The vulnerability of bone tissue to infections and inflammation can significantly impede the bone formation process. Bacterial toxins and invasive enzymes have the potential to damage host cells, thereby exacerbating local inflammatory responses and disrupting bone development (Chen Z. Y. et al., 2021). In pathological states characterized by inflammation and infection, the upregulation of matrix metalloproteinases (MMPs) facilitates the degradation of cartilage tissue, while the inhibition of local angiogenesis contributes to bone loss (Mukherjee and Das, 2024). Consequently, it is imperative to employ effective antibacterial and anti-inflammatory strategies to maintain the osteoimmune environment. The subsequent section explores exogenous strategies for addressing bacterial infections and inflammation.

Employing a combination of therapeutic approaches is a successful strategy to increase osteogenic efficiency. In recent years, numerous MOFs have achieved “1 + 1>2” effects by synergizing the bone-repair functions of their components. Osteoclasts play a pivotal role in bone tissue regeneration by coordinating bone resorption processes, which play a crucial role in bone remodeling and the subsequent creation of new bone tissue (Tsai et al., 2023). Researchers have created novel techniques to control osteoclast activity and enhance bone remodeling by utilizing the distinct characteristics of MOFs. Pang and colleagues enhanced the bone-targeting ability of immunostimulatory CpG-loaded MOF nanoparticles by modifying their surface with zoledronic acid (ZOL), a bisphosphonate approved by the FDA for anti-resorptive purposes (Pang et al., 2020). They observed that CpG oligonucleotides led to a partial inhibition of osteoclast formation and bone resorption, reducing them by about 50%. Significantly, the use of functionalized MOFs (immunostimulatory MOF (isMOF) and BT-isMOF) led to an over 80% reduction in osteoclast formation and entirely eliminated bone resorption activity.

An alternative strategy entails the development of MOF-integrated composite materials designed to modulate ambient pH conditions. These composites have the capability to regulate local pH levels, thereby creating an environment that mitigates excessive osteoclast activation, despite the fact that acidic conditions typically promote osteoclast activity and bone resorption (Jia et al., 2023). Additionally, by fine-tuning the mechanical properties of MOFs, it is possible to engineer a microenvironment that supports osteoclasts, thereby facilitating their physiological functions and contributing to bone remodeling (Wang L. et al., 2020). As a result, the synergistic osteogenic mechanisms demonstrate significantly enhanced bone-forming activity compared to any individual mechanistic component.

Synergistic therapy transcends a mere additive amalgamation of individual osteogenic mechanisms; it represents a complementary integration that leverages the strengths and mitigates the weaknesses of these mechanisms through mutual enhancement, thereby achieving superior osteogenic outcomes.

OP is a common systemic metabolic disease characterized by decreased bone mineral density and bone mass, destruction of bone tissue microstructure, and increased bone fragility, resulting in an elevated risk of fractures.

However, the current conventional approach to treating OP is oral administration of anti-osteoporotic drugs, with drawbacks including first-pass metabolism and gastrointestinal side effects. Moreover, OP may result in microbial infections and necessitates the enhancement of angiogenesis to aid bone repair—such requirements are frequently unaddressed by conventional therapies. Furthermore, oral antibiotics carry the risk of inducing drug resistance during microbial infection treatment (Jiang et al., 2024).

In treating OP, possessing characteristics such as high specific surface area, high porosity, controllable degradability, and variable composition, MOFs not only serve as carriers for controlled drug release and exert multiple effects in treating OP and microbial infections through mechanisms like metal ion release—thus holding inherent advantages for the long-term treatment of OP—but also primarily function to regulate the bone microenvironment, stimulate the growth and differentiation of bone cells, and enhance bone density (Shi et al., 2025; Weng et al., 2024; Xu et al., 2025). For instance, certain MOFs are capable of being used as carriers for the regulated release of drugs (Alsaikhan et al., 2023), exert multi-functional roles in OP-related microbial infections through metal ion release (e.g., Mg²⁺) (Ge et al., 2021), and deliver bioactive factors (Li et al., 2020c).

Notably, Qin et al. developed an innovative hydrogel scaffold inspired by biological systems characterized by a soft-hard composite structure (Qin et al., 2025). This is different from MOFs that serve solely as drug delivery platforms. The structure includes a bilayer MOF, featuring ZIF-67 on the upper layer and ZIF-8 on the lower layer, produced using an in situ printing technique. This configuration enables spatiotemporal regulation of BMSC differentiation by controlling the release of Co²⁺ and Zn²⁺. The stimulation of osteogenic differentiation in BMSCs reduces OP symptoms, demonstrating their inherent benefits for treating OP (Li S. et al., 2024). In vivo experiments were conducted using New Zealand white rabbit models: Firstly, ZIFBH scaffolds (bilayer MOF hydrogels containing 15 mM ZIF-67 and 20 mM ZIF-8) and control scaffolds were subcutaneously implanted. After 2 and 4 weeks, the ZIFBH group showed less inflammatory cell infiltration, with significantly reduced inflammation at 4 weeks; no toxicity was observed in rabbit visceral organs, confirming its good biocompatibility. Secondly, different scaffolds were implanted in a 5 mm × 4 mm osteochondral defect model of rabbit knee joints. After 6 and 12 weeks, the ZIFBH group exhibited the best performance: at 12 weeks, the cartilage surface had minimal fibrosis and good integration with surrounding tissues, achieving the highest ICRS score. The subchondral bone volume fraction and bone mineral density were significantly increased. Immunohistochemistry showed high expression of cartilage-related proteins (ACAN, COL2A1) and osteogenic proteins (RUNX2), forming a complete bilayer repair structure with the highest O’Driscoll score, outperforming scaffolds with single MOF or no MOF.

Bone defects caused by impairment of bone integrity can be divided into congenital deformities and acquired defects resulting from infection, trauma, or tumors. If not treated promptly, they may even lead to amputation (Wei et al., 2024). Therefore, patients bear significant physical, psychological, and economic burdens. Current bone grafting techniques are an effective clinical method for treating patients with large-area bone defects. Although this technique has saved many limbs at risk of amputation, it still has some obvious drawbacks. The main drawback is a prolonged healing period caused by poor osteogenesis and non-union at the bone junction, which may lead to many complications (Wang Q. et al., 2024). Managing these complications will further extend the duration of external fixation. It is well known that long-term wear of external fixators brings great inconvenience to patients, preventing most of them from resuming normal life within a year or even longer.

Simple bone defects have also seen extensive application of MOFs. For instance, Ahmed and colleagues developed UiO-66 nanomaterials that exhibited outstanding cytocompatibility and hemocompatibility, effectively enhancing osteoblast function in vitro (Sadek et al., 2022). Notably, UiO-66 implantation in defects not only demonstrated significant osteoid tissue formation and collagen deposition but also exhibited the potential to upregulate OCN and OPG expression in vivo. Xue et al. demonstrated that iron-based metal-organic framework (Fe-MOF) particles not only inhibit TfR2 but also act as biomimetic catalysts to scavenge hydrogen peroxide from ROS, showcasing their capability as bone regeneration agents. The functions of MOF-Fe included decreasing ROS levels and initiating the BMP signaling pathway (Xue et al., 2024). Wu et al. synthesized bio-MOF-1 coatings on alkali-heat-treated titanium at varying concentrations and systematically evaluated their cytocompatibility and bone development effectiveness in both experimental and natural conditions (Wu et al., 2022a). As a representative bio-friendly MOF with a biologically derived structure, bio-MOF-1 owes its properties to a zinc core and adenine ligands. Exhibiting remarkable thermal stability and biocompatibility, the coating also provided a prolonged release of Zn²⁺, boosting the expression of osteogenesis-associated genes and proteins. In addition, with titanium as the scaffold, the bio-MOF-1 coating on titanium implants substantially improved early osseointegration where the bone meets the implant.

It is noteworthy that in current studies on treating bone defects using MOFs, the bone regeneration efficacy of MOF-based materials has been investigated through animal bone defect models; however, these studies each have distinct focuses and certain limitations. Zhang and his team focused on L-Asp-Cu(II) bio-MOF. In a 5 mm-diameter calvarial defect model of SD rats, surgical implantation of 30 μg/mL L-Asp-Cu(II) significantly increased bone volume fraction (BV/TV) and bone mineral density (BMD) at 8 weeks, and activated the TGF-β/BMP pathway to promote vascularized bone regeneration (Zhang Y. et al., 2025). However, long-term safety and validation in large animal models remain unaddressed. Yu et al. developed a Zn-MOF composite 3D-printed scaffold. In a 3 mm × 4 mm femoral condyle defect model of rats, the PHCZ group achieved a bone volume fraction of 31.39% ± 3.04% at 12 weeks, significantly higher than the control group, and exerted anti-inflammatory-osteogenic synergistic effects by regulating macrophage polarization (Han et al., 2025). Nevertheless, the toxicity risk of long-term Zn²⁺ release and the specific mechanism of MCF require further clarification. Sun et al. targeted aged rat calvarial defects (6 mm diameter). Mg-Ce-MOF scaffolds combined with SKL2001 improved the senescent microenvironment by activating the Nrf2 pathway, with new bone area reaching 42.29% ± 1.87% at 12 weeks (Sun et al., 2025). However, the synergistic mechanism between SKL2001 and MOF, as well as the insufficient sample size of aged models, need further research. However, it is important to emphasize that the significance of their present research lies in modulating the senescent microenvironment (SME) to retard the senescence process of BMSCs, thus offering a viable strategy to facilitate the repair of age-related bone defects. This constitutes a highly intriguing strategy.

MOFs are essential in managing infected bone defects through three primary mechanisms: delivering antimicrobial drugs, leveraging their intrinsic antibacterial properties, and modulating the bone microenvironment (Figure 6). The team led by Ma engineered a sonosensitizer with a defective MOF mediated by alendronate (ALN) (Ma et al., 2024). HN25 increases the accessibility of chromatin for genes related to osteogenesis, such as FOXO1, and aids in bone repair through low levels of ROS when exposed to low-power ultrasound. Rapid clearance of methicillin-resistant MRSA, suppression of osteoclast activity, and enhancement of bone regeneration and differentiation are achieved by this system. In their study, Liu Y. et al. (2025) created a gallium-based MOF (GaMOF) coated with quaternized chitosan (QCS) that carries a positive charge, serving as a “capture agent” to ensnare MRSA by disrupting the TCA cycle (Liu Y. et al., 2025). A radially porous crystal gel embedded with Me and QCSGaMOF was additionally fabricated by them using directional solidification. The oriented porous structure enhances osteointegration by guiding osteoblast ingrowth. Tan et al. synthesized MgCu-MOF-74 nanoparticles with varying Cu content via a one-step hydrothermal method (Liu J. et al., 2022). MgCu-MOF-74 enhances the viability of human osteosarcoma cells (SaOS-2), ALP levels, collagen synthesis, and osteogenic gene expression. Additionally, Cu²⁺-doped samples exhibit heightened sensitivity to acidic microenvironments produced by bacteria, demonstrating stronger antibacterial activity compared to Mg-MOF-74.

MOF-decorated 3D-printed scaffolds have excellent therapeutic advantages for severely defective bones. They not only exert the multiple osteogenic properties of MOFs in osteogenesis but also utilize the scaffolds to avoid the issue that MOFs, being too small at the nanoscale, cannot connect the broken ends of the defect. Zhu and her team focus on Cu-MOF-74-decorated 3D-printed PCL/HAp composite scaffolds, assessing their antibacterial and osteogenic potential in bone defect repair via in vitro experiments (Zhu et al., 2025). Key findings highlight that Cu-MOF-74 concentrations of 0.05%–0.2% balance dual functionalities: the 1% concentration achieves 90.07% and 80.03% inhibition rates against Staphylococcus aureus and Escherichia coli, respectively; low concentrations (≤0.2%) promote the proliferation of rat BMSCs; the 0.05% group shows the highest calcium deposition and osteopontin (OPN) expression; and the 0.2% group exhibits optimal ALP activity. Additionally, Cu²⁺ release follows a biphasic pattern—an initial burst within the first 7 days, followed by sustained release up to 28 days.

Notably, the study has limitations: no in vivo animal experiments were performed to validate efficacy; high concentrations (≥0.5%) of Cu-MOF-74 induce cytotoxicity; and long-term properties of the scaffolds, such as in vivo degradation kinetics and mechanical stability, remain uninvestigated.

Hyperglycemia induces excessive production of ROS in intracellular mitochondria. These ROS directly disrupt the osteogenic microenvironment, interfere with the bone healing process, lead to poor healing of bone defects, and severely impair patients’ quality of life (Khosla et al., 2021; Li X. et al., 2021).

By modulating pathological conditions such as hyperglycemia, oxidative stress, and inflammation, MOFs play a crucial role in the repair of diabetic bone defects, thereby promoting bone regeneration and angiogenesis (Figure 7).

These studies illustrate the extensive potential of MOFs in the context of diabetic bone regeneration, providing innovative strategies for future research and clinical applications. In this regard, Liu et al. developed a Mn@Co₃O₄@Pt nanozyme, designated as MCPtA, which was synthesized from a MOF loaded with alendronate (ALN) and Mg²⁺ (Liu S. et al., 2025). The substitution of Mn atoms into the Co₃O₄ nanocrystal structure modulated the electronic configuration, resulting in a significant enhancement of SOD/CAT catalytic activity. The incorporation of Pt nanoparticles, which mimic glucose oxidase (GOx), enabled MCPtA to effectively perform multi-cascade catalysis, facilitating the clearance of glucose and ROS. This process contributed to the regulation of hyperglycemic conditions and restored the balance between osteoblasts and osteoclasts. By inhibiting inflammatory responses induced by glucose-ROS and promoting the development of bone and vascular tissues, the nanozyme composite hydrogel significantly improved bone regeneration in diabetic patients. Fan et al. introduced a multifunctional bilayer microneedle (d-MNs) system for hard tissue repair. The d-MN matrix is composed of gelatin methacryloyl (GelMA) infused with nano-hydroxyapatite (nHA), which supports osteoblast differentiation and alveolar bone regeneration (Qu et al., 2024). Soft tissue repair is facilitated by a d-MN tip constructed from hyaluronic acid (HA) integrated with a glucose oxidase (GOX)-loaded magnesium Mg-MOF, which imparts both hypoglycemic and anti-inflammatory properties. This dual-functional design ensures a comprehensive therapeutic approach, encompassing hypoglycemic effects, anti-inflammatory responses, neovascularization, and osteogenesis.

Severe tissue dysfunction in diabetic patients represents a tough clinical challenge. Both bacterial infections and chronic inflammation drive disturbances in the diabetic microenvironment and impaired tissue regeneration, thus, there is a greater need for MOFs with composite therapeutic mechanisms. Zhang et al. evaluated the in vivo efficacy of Gelma@Sr-ZIF-8 hydrogel using two diabetic rat models: In the diabetic rat skin infection model (15 mm-diameter infected wounds), local injection of 2wt% Sr-ZIF-8 (Sr/Zn molar ratio 20/100) hydrogel followed by UV curing resulted in a 97% wound healing rate at 14 days, with significantly higher bacterial clearance than the control groups, accompanied by enhanced collagen deposition and angiogenesis. In the diabetic rat femoral defect model (3 mm × 4 mm), 8 weeks after implantation of the hydrogel, the bone volume fraction (BV/TV) reached 38.6% ± 3.2%, significantly higher than the control groups, while promoting M2 macrophage polarization and high expression of osteogenic markers (Runx-2, OCN). Its core advantage lies in the synergistic effects of Zn²⁺ and Sr²⁺ in exerting antibacterial, anti-inflammatory, and bone regeneration-promoting functions with good biosafety (Zhang S. et al., 2025). However, there are limitations: it is only based on rat models without large animal validation; the potential cumulative effects of long-term ion release are unclear; and its repair effect on complex conditions such as diabetes with neuropathy has not been explored.

The studies underscore the substantial potential of MOFs in the context of diabetic bone regeneration, thereby presenting novel strategies for future research and clinical application.

Currently, the primary approach to treating bone tumors is surgical excision, although it often causes local bone defects and tumor recurrence. As a result, it is important to develop biomaterials that can simultaneously address tumor treatment and bone healing after surgery. MOFs, with their unique porous structure, hold significant potential in regenerative medicine and drug delivery. Leveraging their biocompatibility and biodegradability, MOFs can act as drug carriers or sustained-release systems for bioactive factors to promote the renewal and mending of bones. The team led by Qu developed a multifunctional MOF-modified injectable calcium phosphate cement, integrating cobalt-coordinated tetrakis(4-carboxyphenyl) porphyrin (Co-TCPP) (Qu et al., 2021). The inclusion of Co-TCPP not only kept the cement’s superb injectability but also decreased the setting time, boosted compressive strength, and provided the cement with outstanding photothermal capabilities for efficient tumor therapy. This system overcomes the limitation of traditional calcium phosphate cement (CPC), which fails to eliminate residual tumor cells post-surgery, while simultaneously promoting bone and vascular regeneration in vivo, demonstrating ideal osteogenic and angiogenic capabilities. In their study on postoperative therapy, MOF composite scaffolds are also frequently used to meet the requirements of various therapeutic needs. Zeng and colleagues developed a chitosan composite scaffold (CS/DOX@Ti-MOF) aimed at treating tumors and repairing bones (Zeng et al., 2024). The amino-functionalized titanium-based metal-organic framework (NH₂-MIL-125(Ti), Ti-MOF) exhibits a high specific surface area (1,116 m²/g) and excellent biocompatibility, enabling the loading of doxorubicin (DOX), a chemotherapeutic agent while promoting osteogenic differentiation. The composite scaffold demonstrates improved physical mechanical properties and a rough surface, facilitating cell adhesion. In the tumor microenvironment, the scaffold releases DOX in a responsive manner to destroy residual tumor cells and then provides areas for cell attachment, growth, and differentiation. This dual functionality enhances bone repair and achieves adjunctive therapy for postoperative bone tumors. In their study, Yuan J. et al. (2023) focused on the interaction between DOX and MOFs for bone tumor therapy, designing amino-functionalized zirconium MOF nanoparticles containing DOX (DOX@UiO-66-NH₂ NPs). Lung injury was significantly reduced by DOX@UiO-66-NH₂ NPs in vivo compared to free DOX. Notably, internalized UiO-66-NH₂ NPs markedly activated the PI3K-Akt and MAPK signaling pathways, promoting osteogenic differentiation of pre-osteoblasts. UiO-66-NH₂ nanoparticles are positioned as a multifunctional nanomaterial for both bone tumor treatment and the enhancement of bone growth.

MOFs feature ultra-high specific surface areas and adjustable porous architectures (e.g., ZIF-8 with a specific surface area reaching 1700 m²/g), facilitating high-efficiency loading of diverse therapeutic agents (including antibiotics, growth factors, and metal ions). Their drug-loading capability exhibits marked superiority over that of conventional carriers such as chitosan and MSN. The pore dimensions and topological structures of MOFs are amenable to precise modulation, preventing abrupt drug release and thereby enabling sustained and controlled release profiles (Xu H. et al., 2024). For instance, ZIF-8 can undergo pH-responsive degradation (structural disintegration in acidic microenvironments) to slowly release loaded bisphosphonates or zinc ions, matching the long-term requirements of bone regeneration (Yun et al., 2025). In contrast, the release rate of polymer nanoparticles such as PLGA is difficult to precisely control, prone to early burst release or insufficient late-stage release.

MOFs are capable of exerting diverse biological functionalities concurrently via the integration of metal ions and organic ligands, whereas most traditional nanoparticles have relatively single functions.

MOFs can significantly reduce toxicity risks by selecting endogenous metal ions (e.g., Zn²⁺, Mg²⁺, Ca²⁺) and biodegradable organic ligands (e.g., imidazole, carboxylic acid). In addition, the degradation rate of MOFs can be adjusted by ligand stability (e.g., controlling the degradation rate by changing ligand chain length), matching the dynamic balance of “material degradation-new bone formation” during bone regeneration (Farjaminejad et al., 2024). In contrast, inorganic nanoparticles such as HA degrade slowly and tend to remain for a long time.

MOFs are rich in active functional groups (e.g., amino, carboxyl) on their surfaces, allowing convenient targeted modification (e.g., conjugation with bisphosphonates or bone-targeting peptides) to enhance specific accumulation at bone defect sites (Li et al., 2024a). For example, ZOL-modified ZIF-8 nanoparticles can achieve bone-targeted delivery through high affinity with hydroxyapatite in the bone matrix, reducing side effects on other tissues (Choi et al., 2023). In contrast, targeted modification of traditional nanoparticles (e.g., liposomes, micelles) is more complex and less stable.

The structures of MOFs can be flexibly tailored by adjusting metal ion types, ligand species, and synthesis conditions, enabling intelligent response to the microenvironment (e.g., pH, temperature, enzymes) (Choi and Paul, 2025). For instance, in the acidic microenvironment of bone infection, MOFs can rapidly degrade and release antibiotics; in the neutral environment of normal bone tissue, they remain stable to reduce drug waste (Feng et al., 2024). This responsiveness is significantly superior to PLGA or CS nanoparticles, which lack environmental sensitivity.

Biocompatibility is one of the most critical considerations in biomaterial design, indicating a material’s ability to carry out its function without triggering toxic or harmful reactions in biological systems while inducing an appropriate host response under specific conditions (Lu et al., 2023). Today, the concept of biocompatibility encompasses not only bio-inertness but also biofunctionality and bio-stability (Huzum et al., 2021), such as hemocompatibility, histocompatibility, and immune responses. However, a primary concern for MOF-based nanomaterials is their uncertain biocompatibility. Due to the diverse physicochemical properties of MOFs and their complex interactions with cells, efficacy does not equate to safety. Many MOFs still face biocompatibility-related challenges. For instance, the surface charge of MOF nanoparticles can attract plasma proteins, leading to unusual blood clotting and the breakdown of red blood cells (Zheng et al., 2024). Toxicity can also be caused by the excessive local release of metal ions or drugs from MOFs.

Jiang et al. synthesized micro/nano-scale bio-functional entities (m/n-bio-MOF-1) using a modified method and systematically evaluated them across multiple dimensions, covering cell multiplication, oxidative stress, apoptosis, and animal trials (Jiang et al., 2022). Reducing the concentration of n-bio-MOF-1 resulted in smaller particles, which enhanced cell adhesion, improved morphology, lowered in vitro cytotoxicity, decreased ROS induction, and increased stability. Beyond modifying the MOF framework itself, surface functionalization can also enhance biocompatibility. For instance, PEGylation (polyethylene glycol modification) of MOFs improves intracellular stability and enables delayed drug release with reduced cytotoxicity (Chen X. et al., 2021; Li et al., 2023b).

Therefore, two critical aspects warrant consideration when improving the biocompatibility of MOFs. First and foremost, it is critical to assess the metabolic profiles of MOF particles in vivo to clarify whether their metabolic byproducts pose health hazards and to guarantee their safe and efficient excretion (Singh et al., 2021). A second key consideration centers on the hemocompatibility of MOF particles, which may trigger blood coagulation, hemolysis, or abnormal platelet activation upon administration. The hemocompatibility of MOF particles is primarily shaped by parameters including surface charge, size, and morphology, which are amenable to optimization via targeted modifications.

Apart from ensuring biocompatibility, the production of MOFs with high purity is a major challenge for their market and medical application. In biomedical applications, MOF purity is paramount. However, conventional synthesis methods often involve toxic solvents and impurities, necessitating the development of green synthesis approaches. Solvothermal methods and post-synthetic modifications frequently suffer from inconsistent reaction conditions (temperature, pressure, precursor ratios), leading to insufficient product purity. In catalytic applications, improper design of MOF pore structures—such as excessively narrow pores or uneven metal loading—can trap intermediate products, triggering side reactions and complicating the isolation of pure MOF materials. In this scenario, laser-induced synthesis has become a revolutionary technology (Guo et al., 2023). This high-efficiency pyrolysis technique enables the production of purer MOFs compared to traditional hydrothermal/solvothermal methods. Major benefits are quick processing, accuracy, minimal waste, high efficiency, selectivity, and programmability, which give MOF derivatives new functionalities. Laser-synthesized MOFs show improved crystallinity and defect management, positioning them as promising options for cutting-edge biomedical and catalytic uses.

The precise modulation of MOF parameters is crucial for attaining desired therapeutic outcomes in osteogenic treatments (Manzari et al., 2021). Critical factors, including MOF concentration, pore size, drug loading capacity, and active site configuration, necessitate meticulous optimization. Furthermore, improving the targeting specificity of MOFs for various osteogenic-disrupting pathologies is vital to ensure accurate recognition of diseased tissues. MOFs that incorporate multiple osteogenic mechanisms typically demonstrate enhanced laboratory performance and exhibit greater potential for clinical translation. In the following discussion, we concentrate on strategies for adjusting pore size.

Osteogenic MOFs are taken up by osteoblasts in a manner significantly influenced by the size effect. Cells tend to internalize smaller-sized nanoparticles, suggesting that rational adjustment of MOF dimensions can enhance their uptake by bone-related cells (Xue Y. et al., 2021). Additionally, miniaturization increases interactions between MOFs and cellular components, thereby boosting osteogenic capabilities (Batool et al., 2023). Ahemed et al. successfully synthesized Zn-MOF/bioactive glass (BG) nanoparticles using a rapid alkali-modified sol-gel method (Ahmed et al., 2024). In comparison to standalone BG, the BG/Zn MOF composite demonstrated superior antimicrobial activity and prolonged drug release. Nano-ZIF-8 membranes further enhanced ALP activity, extracellular matrix mineralization, and osteogenic gene expression. Compared to larger Zn-MOFs, the nano-sized Zn-MOFs exhibited higher specific surface area and improved dispersibility. Moreover, they facilitated hydroxyapatite formation, contributing to effective bone regeneration. Nonetheless, the efficient cellular absorption of nano-sized MOFs suggests they might infiltrate cell membranes and gather in healthy cells, which could be hazardous to human health.

By carefully designing the pore sizes of MOFs, their effectiveness as carriers for drug molecules, such as osteogenic inducers and antibiotics, can be improved to aid in bone regeneration. For successful drug incorporation, the pore dimensions of MOFs should match the size of drug molecules, which can differ. Deng and colleagues created an innovative multifunctional photosensitive yolk-shell nanoparticle that responds to stimuli by selectively etching a biodegradable crystalline ZIF-8 shell around a star-shaped gold nanoparticle photothermal yolk using tannic acid (Deng et al., 2019). The findings indicated that the ZIF-8 shell became significantly thinner, creating additional space between the Au nanoflowers and the MOF framework. Compared to core-shell ZIF-8@Au structures, this yolk-shell configuration exhibited substantially enhanced drug-loading capacity.

MOFs have not yet been successfully commercialized within biomedical applications. One of the core obstacles to the commercialization of MOFs is the high production cost and significant difficulty in scaling up, which mainly stem from the cost of raw materials, synthesis efficiency, and the complexity of downstream processing (Barsoum et al., 2025). In the field of biomedicine (such as bone implantation), commercialization needs to address issues like metal ion toxicity, controllability of degradation, and immune responses (Wright et al., 2025). Moreover, it is necessary to optimize performance for specific scenarios; for example, bone implants require a balance between mechanical strength and osteoconductivity (Chen Z. et al., 2021). Finally, there exist problems in the MOF field such as a disconnect between research and industrialization, as well as insufficient interdisciplinary collaboration,all of which have impeded the widespread adoption of MOFs in the biomedical sector (Liu Y. et al., 2024). Nonetheless, with ongoing advancements in MOF research, it is anticipated that their biocompatibility will continue to improve, and biosafety will be further enhanced, thereby establishing a foundation for future biomedical applications. Although MOFs possess significant potential for medical applications, existing limitations must be addressed. Progress in research and technology is expected to help overcome these challenges, ultimately unlocking the precise therapeutic capabilities of MOFs in the field of nanomedicine. Recently, 3D printing technology has been applied to bone implantation. By constructing porous structures with a porosity of 50%–80%, it can match the mechanical properties of cancellous bone (with a compressive strength of 10–30 MPa) while promoting cell infiltration. In addition, composite biomaterials are used, which are compounded with natural polymers (such as collagen and chitosan) or degradable polymers (such as PLGA and PCL). This not only reduces immunogenicity but also matches the bone regeneration cycle (usually 8–12 weeks) (Li M. et al., 2022; Pourmadadi et al., 2023).