Introduction

The management of illnesses using therapeutic substances has been a subject of significant interest for an extended period. Although traditional methods of drug delivery offer some therapeutic benefits, they have inherent disadvantages. These include fluctuations in drug plasma levels and rapid elimination from the body due to premature metabolism and excretion (Masoudifar et al. 2022). For example, Li et al. (2015) engineered a pH-modulated solid dispersion loaded with flurbiprofen, forming the basis of an osmotic pump capsule for controlled drug delivery. They conducted a pharmacokinetic evaluation of this formulation compared to commercial conventional flurbiprofen tablets in beagle dog subjects. The area under the curve (AUC0-t) for the osmotic pump capsule and the commercial tablet were 847.6 and 632.5 µg h/mL, respectively, with a relative bioavailability of 134% compared to that of the marketed preparation. The improved drug absorption could be attributed to the amorphous form of the drug in the capsule, leading to enhanced solubility and rapid absorption. Notably, the peak plasma concentration (Cmax) for the osmotic pump capsule was 59.3 µg/mL, which was significantly lower than that of the conventional tablet (94.5 µg/mL), thereby mitigating side effects. Moreover, the time to reach peak plasma concentration (Tmax) was extended from 2 to 8 h. These pharmacokinetic comparisons underscored the successful control of flurbiprofen release by the novel osmotic pump capsule, resulting in minimized plasma concentration fluctuations. Consequently, this preparation has advantages in extending drug action and reducing the frequency of drug administration (Li et al. 2015). Additionally, the nontargeted dispersion of drugs throughout the body not only reduces the drug concentration at the intended site but also leads to adverse side effects on healthy tissues and organs (Tran et al. 2017). Bishnoi et al. (2021) developed nanovesicles loaded with tapentadol HCl (TAP) and targeted them with chondroitin sulfate (CS) for treating osteoarthritis (OA). The effectiveness of the resulting formulation (C-MB-NV) was compared to that of a nontargeted formulation (MB-NV). The results indicated improved pharmacokinetic parameters for C-MB-NV compared to those of MB-NV and TAP solutions (t1/2: 9.7, 11.505, and 0.9807 h; AUC: 159.725, 139.86, and 25.315 µg h/mL; and mean residence time (MRT): 14.99, 13.873, and 1.328 h for C-MB-NV, MB-NV, and TAP solutions, respectively), showing enhanced bioavailability and analgesic effects in a rat model of OA by exploiting CD44 receptors. The recovery rates of MB-NV and C-MB-NV in the knee joint after 4 h were 2.08% and 4.89%, respectively, and after 24 h, they were 1.32% and 2.01%, respectively. CS-conjugated MB-NV could deliver the loaded drug specifically to cartilage cells with minimal undesirable side effects and reduced habit-forming tendencies. This suggests that C-MB-NV could serve as a targeted antinociceptive/analgesic agent for infected bone joints, minimizing disruption to healthy tissues (Bishnoi et al. 2021).

The development of innovative drug delivery systems (DDSs) has introduced new possibilities for enhancing the pharmacokinetic characteristics of loaded therapeutics (Ebrahimi Shahmabadi et al. 2014; Alavi et al. 2019, 2020; Alavi and Shahmabadi 2021), particularly in terms of drug absorption and biodistribution (Patra et al. 2018). These new DDSs exhibit notable advantages, including enhanced bioavailability, increased loading capacities, and improved drug accumulation at target sites. They achieve this by releasing their payloads in a controlled manner, thereby minimizing the presence of drugs in healthy tissues (Patra et al. 2018; Alavi et al. 2021; Boshrouyeh et al. 2023; Alavi et al. 2024b; Alrashidi et al. 2024). These attributes, such as reduced dosing frequency, consistent drug plasma concentration, and prolonged half-life, contribute to enhanced patient convenience and compliance (Masoudifar et al. 2022).

Metal–organic frameworks (MOFs) have received attention because of their remarkable chemical and physical properties (Table 1) (Munawar et al. 2023). These materials, with an evolutionary history of approximately 300 years (Fig. 1), are promising candidates for various biomedical applications, particularly in drug delivery, biosensing, and disease diagnosis (Munawar et al. 2023). The trend depicted in Fig. 2 over a decade from 2012 to 2022 indicates a growing research focus on MOFs for biomedical uses (Nguyen et al. 2024). Additionally, they demonstrate numerous benefits, including a well-defined structure, a broad range of pore specifications, high porosity, low toxicity, easy functionalization, and adjustable frameworks (Al Sharabati et al. 2022). Moreover, nanocarriers have been used for targeted drug delivery, demonstrating several advantages, such as biostability, dynamic strength, prolonged circulation in the bloodstream, reduced toxicity, biodegradability, intrinsic stability, and unique electronic properties (Ghezzi et al. 2021; Koohi Moftakhari Esfahani et al. 2022; Munawar et al. 2023).

Table 1 Physicochemical properties of metal–organic frameworks (MOFs)
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Fig. 1
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Historical development of MOFs (Tomic 1965; Hoskins and Robson 1990; Yaghi et al. 1995; Li et al. 1999; Kesanli and Lin 2003; Uemura et al. 2005; Gascon et al. 2008; Eddaoudi et al. 2015). Reprinted with permission under a Creative Commons [CC-BY 4.0] from ref. (Gatou et al. 2023). Copyright [2023] [MDPI]

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Fig. 2
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Reproduced with permission from ref (Nguyen et al. 2024). Copyright 2024 RSC

Number of publications on the biomedical applications of MOFs.

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In the realm of drug delivery, MOFs exhibit potential as carriers for various substances, including small molecule drugs, proteins, and nucleic acids (Table 2). These hybrid materials, characterized by their porosity and adjustability, possess diverse properties, notably a substantial surface area (Gautam et al. 2023). The significant surface area facilitates a high capacity for drug loading and the ability to tune the pore size and structure enables control over drug release rates, enhancing drug stability (Scicluna et al. 2020). Furthermore, the biocompatibility and biodegradability of MOFs make them appealing for in vivo applications. An illustrative example involves the use of MOFs for delivering anticancer drugs, where they enhance drug solubility and stability, leading to improved therapeutic efficacy (Jin et al. 2020). Additionally, MOFs can be modified with targeting components to selectively deliver drugs to cancer cells (Fig. 3) (Alijani et al. 2020). Another application is the delivery of antimicrobial agents, where MOFs can be engineered to release these agents in a controlled manner, decreasing the risk of resistance development (Livesey et al. 2023). Figure 4a depicts a general approach to employing MOFs as a targeted drug carrier system under in vivo conditions.

Table 2 Application of metal–organic frameworks (MOFs) for the delivery of various therapeutic compounds for the treatment of various diseases
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Fig. 3
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Reproduced with permission from ref (Alijani et al. 2020). Copyright 2020 Elsevier

Representation of targeted drug delivery. The diagram shows the synthesis and utilization of a nanocarrier for targeted drug delivery. At the top, the process of creating UiO-66-NH2 MOF on magnetic Fe3O4 nanoparticles was demonstrated, followed by modifications, including the loading of doxorubicin (DOX), the encapsulation of carbon dots, and the attachment of a nucleolin-binding aptamer (AS1411). The bottom image shows how the Fe3O4@MOF-DOX-CD-Apt nanocarriers are taken up by nucleolin-overexpressing triple-negative MDA-MB-231 human breast cancer cells through nucleolin-mediated interactions. Additionally, it shows the pH-triggered release of DOX in the lysosomes or endosomes of cancer cells.

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Fig. 4
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a Illustration of the fundamental approach for using metal–organic frameworks (MOFs) for selective drug delivery. b Visual representation of systematic antitumour agents involving MOFs and drugs. The figure shows three types of MOF-drug synergistic systems: active ligands + drugs, active nodes + drugs, and active nodes and ligands + drugs

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Additionally, the incorporation of functional groups onto MOFs is expected to exert a significant influence on the development of novel multifunctional composites and hybrid materials. These modified materials are anticipated to demonstrate distinct properties, rendering them superior to their original forms, with enhanced and improved synergistic effects (Awasthi et al. 2022).

This review provides a comprehensive overview of recent advancements in utilizing nano-MOFs for nanomedical purposes, particularly for drug delivery. The benefits of MOFs in delivering diverse drug compounds, including their properties, such as composition, structure, porosity, and surface area, are emphasized. Various aspects, including drug delivery characteristics, synergy with other compounds, stability, synthesis techniques, characterization methods, and surface functionalization for enhanced drug loading, are discussed. This review thoroughly explores controlled release mechanisms, targeted delivery, stimuli-responsive release, biocompatibility, toxicity, strategies for enhancing biocompatibility, and the current landscape of clinical trials. Moreover, this study addresses challenges in the use of MOFs for drug delivery and suggests future research directions to address these hurdles.

Fundamentals of nano-MOFs

Overview of MOFs

MOFs, or coordination polymers formed from metal ions and organic linkers, exhibit diverse traits, such as high porosity, significant surface area, and large pore volume. With unique chemical and thermal stability (Maranescu and Visa 2022), MOFs have applications in gas storage (Li et al. 2019), photochemistry (Young et al. 2023), catalysis (Bazaga-García et al. 2021), flame retardancy (Nabipour et al. 2020), corrosion protection (Maranescu et al. 2019), separation processes (Zhang et al. 2021b), adsorption (Baby et al. 2022), diagnostics (Al Sharabati et al. 2022), antimicrobial functions (Pettinari et al. 2021), and drug delivery (Vassaki et al. 2021). These attributes position MOFs as highly promising materials in the field of biomedicine (Maranescu and Visa 2022).

Composition and structure of the MOFs

MOFs can be classified according to various factors, such as their composition, structure, and applications (Table 3).

Table 3 Various types of metal–organic frameworks (MOFs) categorized based on their composition, structure, and applications
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Porosity and surface area

MOFs exhibit a diverse array of visually appealing framework topologies and distinctive structural characteristics, including expansive surface areas, adjustable porosity, and the potential for targeted incorporation of functional groups into their framework (Ahmed et al. 2022). The design, customization, and modification of MOFs involve adjusting structural parameters, such as metal clusters, organic linkers, and pore sizes, to achieve significantly high surface areas, high-porosity crystalline structures, a high density of active sites, and notable stability (Moharramnejad et al. 2023).

MOFs are categorized as microporous, mesoporous, or macroporous based on their internal pore width. This classification aligns with the International Union of Pure and Applied Chemistry (IUPAC) categorization of porous materials, which correlates the confined pore size with the guest molecules encapsulated during a physisorption process (Ahmed et al. 2022). According to this definition, the majority of MOFs are considered microporous (pore width < 2 nm), with a limited number being mesoporous (pore width between 2 and 50 nm). Notably, there have been recent reports of MOF composites falling within the macroporous range (pore width > 50 nm) (Feng et al. 2021; Ahmed et al. 2022).

Nanoparticles in drug delivery

A particle with dimensions smaller than 100 nm is classified as a nanoparticle. Nanostructures of this size exhibit a significant surface-to-area ratio, display quantum effects, and demonstrate high mobility when in a free state (Sharma et al. 2021). Traditional drugs encounter issues, such as limited specificity, low bioavailability, and elevated toxicity. These challenges can be significantly addressed through the utilization of DDSs based on nanoparticles (Babaei et al. 2017; Sharma et al. 2021; Alavi et al. 2022c, 2023, 2024c; Ghaferi et al. 2022).

Engineered nanoparticles can possess specific surface properties that enable them to selectively target diseased cells, minimizing the impact on healthy cells. This targeted approach enhances drug efficacy and reduces potential side effects (Esfahani et al. 2021; Yusuf et al. 2023). Moreover, nanoparticles can be designed to release their contents in a controlled manner, facilitating sustained drug delivery over an extended period (Bajpai et al. 2018; Alavi et al. 2022a, 2022c; Alharthi et al. 2024). Beyond therapeutic applications, nanoparticles find utility in diagnostics, serving as contrast agents in medical imaging or aiding in the detection of specific biomolecules in biological samples (Kalra et al. 2021). In the field of regenerative medicine, nanomaterials serve as scaffolds for tissue engineering and as carriers for growth factors, fostering tissue repair and regeneration. Despite being in its early stages, the field of nanomedicine holds significant promise for enhancing the diagnosis and treatment of various medical conditions (Alavi et al. 2022d, 2024a; Yusuf et al. 2023).

Types of nanoparticles

Nanoparticles are commonly categorized into material-based groups, specifically organic, inorganic, and carbon-based groups, based on their chemical properties.

Organic matter-based nanoparticles

Traditionally, organic-based nanoparticles dominate the nanoparticle category, utilizing noncovalent interactions for self-assembly and molecular design. This facilitates the formation of specific structures, such as dendrimers, micelles, liposomes, ferritin, or polymers (Alavi et al. 2014, 2022b; Dadgar et al. 2014; Koohi Moftakhari Esfahani et al. 2018; Sahu et al. 2021). Notably, these nanoparticles are biodegradable and nontoxic. Some, such as nanocapsules with hollow cores (e.g., micelles and liposomes), are sensitive to thermal and electromagnetic radiation, making them ideal for targeted drug delivery in biomedical applications (Sahu et al. 2021).

Inorganic matter-based nanoparticles

Inorganic nanoparticles, devoid of a carbon skeleton, predominantly consist of metal ions (Al, Cd, Co, Cu, Au, Fe, Pb, Ag, and Zn), along with metal oxides. Metal-based nanoparticles are derived from nanometric-sized metals through destructive and constructive methods (Heuer-Jungemann et al. 2019) and exhibit unique properties, such as sizes ranging from 10 to 100 nm, high surface area-to-volume ratios, various structures, and susceptibility to environmental factors. In contrast, metal oxide-based inorganic nanoparticles synthesized in the presence of oxygen include compounds, such as aluminum oxide, cerium oxide, iron oxide, magnetite, silicon dioxide, titanium oxide, and zinc oxide. These metal oxide nanoparticles, which exhibit heightened reactivity (Nikolova and Chavali 2020), possess notable bioavailability, allowing easy modification through chemical reactions, such as polymer chain incorporation, coupling agents, or metal ion doping (Das et al. 2020).

Carbon-based nanoparticles

Carbon-based nanoparticles, including carbon nanotubes, nanofibers, fullerenes (C60), graphene, and carbon black, exhibit diverse chemical and physical properties, such as stability, conductivity, and thermal characteristics. Renowned for their versatility, these nanoparticles play crucial roles in various fields (Kaushik 2019), from medical imaging and cosmetics science to water purification, photovoltaics, electronics, and composite reinforcement (Sahu et al. 2021).

Advantages in drug delivery

The utilization of nanoparticles as a DDS is still in its early stages of development. Nevertheless, nanotechnology presents a promising solution to address various clinical limitations commonly encountered in the development of pipeline drugs. These nanoparticles exhibit noteworthy physicochemical and biological properties (Table 4) that offer significant advantages for drug delivery (Gatto and Najahi-Missaoui 2023). Studies (Miranda et al. 2021; Vajedi et al. 2021) have demonstrated their ability to enhance drug solubility, reduce treatment toxicity, improve the targeted delivery of drugs, and regulate the rate of drug release (Gatto and Najahi-Missaoui 2023).

Table 4 Biological functions of metal–organic frameworks (MOFs) for drug delivery
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Miranda et al. (2021) synthesized a lapachol (LAP)-loaded nanoemulsion (NE, NE-LAP) for the targeted delivery of LAP, a poorly soluble compound. NE-LAP, with an encapsulation efficiency of more than 85%, effectively addressed the solubility issue of the compound. Biodistribution studies demonstrated an increase in the tumor-to-muscle drug ratio over time, reaching a maximum of 6.5 after 24 h, indicating that LAP preferentially accumulated in tumor tissue. Additionally, drug release studies revealed that NE-LAP exhibited more sustained release than free LAP. When 100% of the free LAP was released within ~ 1.5 h, NE-LAP released 100% of the loaded LAP after 6 h. Furthermore, a toxicity evaluation demonstrated that compared with the control group, the NE-LAP receiver group did not show any alterations in biochemical parameters (creatinine, urea, alanine aminotransferase x(ALT), and aspartate aminotransferase (AST)) in 4T1 tumor-bearing mice, indicating a lack of potential dose-limiting organ toxicity. Histological analysis corroborated these findings, as no notable changes were observed in liver or kidney tissue (Miranda et al. 2021).

Synergistic effects of nano-MOFs

Active MOFs can be manipulated to interact with drugs, facilitating the development of intelligent or multifunctional drug-MOFs and leading to synergistic systems (Ni et al. 2020). Combining bioMOFs with other active components, such as 5,10,15,20-tetra(p-benzoato)porphyrin (TBP) and cytosine-phosphate-guanosine (CpG) (Ni et al. 2020), as well as porphyrin-based MOFs and manganese ferrite nanoparticles (MnFe2O4) (Yin et al. 2019), enhances therapeutic efficacy. For instance, compared with blank nanoparticles, TBP-CpG-loaded nanoparticles reduced tumor weight in breast cancer-bearing mice by ~ 10.2-fold (Ni et al. 2020), while compared with phosphate-buffered saline (PBS) + laser, MnFe2O4@MOF + laser decreased tumor volume in breast cancer-bearing mice by ~ 80-fold (Yin et al. 2019), creating robust systems with improved selectivity and safety (Yin et al. 2019; Ni et al. 2020). This innovation expands the applications of MOF-based antitumour agents (Fig. 4b) (Gao et al. 2021). MOF-drug synergistic systems are classified into three types based on their intrinsic structure: (i) drug-node synergistic systems, (ii) drug-linker synergistic systems, and (iii) multiplex synergistic systems (Gao et al. 2021).

Improved stability and encapsulation efficiency

MOFs, known for their high surface area and porosity (1000 to 10,000 m2/g), enable increased biomolecule loading and diverse pharmaceutical encapsulation (Al Sharabati et al. 2022). Although limited stability often poses challenges to the effective utilization of MOF materials (Cai et al. 2022b), recent research (Horcajada et al. 2008) indicates that certain MOFs exhibit stability under physiological conditions. For instance, Horcajada et al. (2008) utilized flexible nanoporous chromium or iron terephthalates (benzenedicarboxylate, BDC), specifically MIL-53(Cr, Fe) or M(OH)[BDC], as matrices for the adsorption and in vitro delivery of ibuprofen. Both MIL-53(Cr) and MIL-53(Fe) solids adsorb ~ 20 wt% ibuprofen, suggesting that the quantity of inserted drug remains independent of the metal constituting the hybrid framework. These MOFs achieved a deliberate, gradual release of ibuprofen under physiological conditions over a period of 3 weeks, displaying predictable zero-order kinetics. Compared to other materials (e.g., Mobil Composition of Matter No. 41 (MCM-41), MCM-41prop-NH2 (MCM-41pr-NH2), and MIL-101), MIL-53 exhibited superior preservation of the loaded ibuprofen, releasing the total loaded drug after ~ 434 h. This underscores the exceptional ability of flexible hybrid solids to optimize interactions between the drug and the matrix. Furthermore, the overall stability of MOFs is typically enhanced when various metal ions are linked by diverse coordinating ligands, influencing MOF structures through their coordination geometry (Yusuf et al. 2022).

Synthesis and characterization of nano-MOFs

Methods for synthesizing nano-MOFs

The development of micro/nano-MOFs is influenced by various factors, including metal precursors, organic linkers, solvents, templates, and reaction parameters (e.g., temperature and time), offering significant possibilities for fine-tuning the micro/nanostructure of desired products (Usman et al. 2020; Wang et al. 2022a).

In recent years, diverse methodologies have emerged for developing micro/nano-MOFs with various morphologies. Some of these techniques are extensively utilized and exhibit robust applicability in synthesizing MOFs with specific structures (Meng et al. 2023). For instance, various successful methods have been developed for producing one-dimensional (1D) micro/nano-MOFs, including coordination modulation, templating approaches, and microfluidics (Meng et al. 2023). By employing these techniques, a range of well-performing 1D micro/nano-MOFs, such as nanowires, nanorods, and nanofibers, have been successfully constructed (Okada et al. 2020). Strategies, such as interfacial synthesis and exfoliation methods, have been confirmed to be valuable for the synthesis of two-dimensional (2D) micro/nano-MOFs (Zhao et al. 2017). Techniques, such as etching and spray drying, are effective for the synthesis of porous micro/nano-MOFs (Chaudhari et al. 2017; Kaneti et al. 2017).

The approaches for creating nano-MOFs are generally divided into three categories: bottom-up, top-down, and hybrid approaches (Fig. 5; Table 5). Bottom-up techniques often employ two methods to reduce the size of MOFs (Zhong et al. 2021): (i) adjusting reaction parameters, including metal ion and ligand concentrations, their ratio, pH, solvent, types of metal salts, temperature, and time; and (ii) introducing coordination reagents, such as acids, bases, inorganic salts, and surfactants. On the other hand, top-down techniques involve producing nanoscale structures through etching methods, such as liquid exfoliation and salt-template confinement (Zhong et al. 2021).

Fig. 5
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a Top-down and bottom-up and b hybrid synthesis of nanoparticles. In top-down approaches, nanoparticles are synthesized from bulk MOFs through size reduction methods (e.g., ultrasonic exfoliation, chemical exfoliation, and mechanical exfoliation), while in bottom-up approaches, nanoparticles are formed through the assembly of smaller starting materials, such as atoms, ions, molecules, and clusters, using methods, such as reaction parameter-assisted synthesis, coordination-assisted synthesis, and hydrothermal methods. In the hybrid approach, various modifications, such as covalent and noncovalent methods, as well as the use of MOFs as sacrificial templates or precursors, have been employed to develop MOF hybrids

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Table 5 Overview of methods for synthesizing nano-MOFs
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Bottom-up synthesis

Bottom-up approaches, such as reaction parameter-assisted synthesis and coordination-assisted synthesis, typically commence with precisely crafted metal ions/clusters and organic linkers, capitalizing on the inherent tailorability of MOFs (Zhong et al. 2021). These approaches share similarities with self-assembly, a process that combines small atomic or molecular components to develop intricate nanoscale assemblies or directed self-assemblies using sophisticated mechanisms and technologies. The vital aspect of this approach lies in controlling the nucleation rates of distinct crystal facets by selectively constraining growth in either the horizontal or vertical direction (Zhong et al. 2021).

Kiadeh et al. (2021) synthesized a modified Cu-based MOF containing folic acid and incorporated it into pectin electrospun nanofibers, which not only improved the release behavior of copper ions by ~ 20.5-fold (Fig. 6a) but also enhanced the strength of the fiber mat (increasing the tensile strength by 2.8-fold) and imparted antibacterial properties (p value < 0.05) due to the loaded copper ions and folic acid. In summary, the incorporation of modified Cu-based MOFs containing folic acid into pectin electrospun nanofibers not only addressed the challenge of poor mechanical strength associated with pectin drug carriers but also improved antibacterial properties, angiogenesis induction, and fibroblast migration, making these MOF-containing pectin nanofibers promising for biomedical applications.

Fig. 6
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Reproduced with permission from ref. (Kiadeh et al. 2021). Copyright 2021 Elsevier. b In vitro lansoprazole nanosheet release profile at various pH values, including 4.5, 7.4, and 8.4. Reproduced with permission from ref. (Qasem et al. 2023). Copyright 2023 ACS. c The impact of MIL-101(Fe)@FU@FA on the migration of SMMC-7721 cells was evaluated, and the results were compared with those of MIL-101(Fe)@FU, 5-FU, and a control group. As shown in the figure, the loading of 5-FU into MIL-101(Fe)@FU and MIL-101(Fe)@FU@FA nanoparticles increased the inhibitory effects of 5-FU on SMMC-7721 cell migration by ~ 32.3 and ~ 61.3%, respectively. Reproduced with permission from ref. (Xie et al. 2022). Copyright 2022 Elsevier

a Quantification of Cu+2 ions released from the samples after immersion in PBS for 1, 2, 3, 4, 5, 7, and 9 days, indicating the advantageous slow release of Cu+2 in the pectin/PEO/F-Hkust mats (FK-4000–1).

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Top-down synthesis

In top-down methodologies, the layers of MOFs connected through weak interactions can be separated into individual nanosheets through methods, such as mechanical exfoliation, chemical exfoliation, sonication exfoliation, and metal intercalation. The exfoliation process, which includes mechanical shaking, ball milling, and ultrasonic treatment, is the most frequently utilized top-down technique (Arun Kumar et al. 2021).

Qasem et al. (2023) synthesized a 2D MOF, known as 2D Cu-MOF, using 4,4′-trimethylenedipyridine as the organic linker. The resulting MOF, composed of tangled layers, was easily separated through ultrasonication-induced liquid phase exfoliation (UILPE), yielding 2D Cu-metal–organic nanosheets (2D Cu-MONs). The potential of these 2D Cu-MONs as a DDS for the treatment of peptic ulcers was then evaluated, and they demonstrated remarkable drug loading (45.6%) of lansoprazole. The release of the loaded drug in both acidic (79.50% at pH 4.5) and neutral (87.40% at pH 7.4) media highlighted that the 2D Cu-MONs are excellent carriers for antiulcer drug delivery (Fig. 6b). Notably, the increased surface area achieved through UILPE was attributed to high drug loading. The results of this study (Qasem et al. 2023) indicated that the developed 2D Cu-MONs hold promise for applications in the field of drug delivery.

Hybrid approaches

In hybrid methodologies, a combination of top-down and bottom-up fabrication techniques is employed to create nanostructured platforms. The production of these hierarchically organized structures using exclusively top-down or bottom-up methods is typically challenging or unfeasible (Harish et al. 2022). One illustration is the expulsion of variously sized fragments by volcanoes, spanning from nanofragments to nanoparticles. These materials are considered "top-down" incidental nanomaterials, with smaller fragments serving as precursors that could engage in a "bottom-up" process to generate a different type of material (Barhoum et al. 2022).

An illustration of a hybrid approach is photolithography, where etching serves as the top-down technique, and layer formation through ion growth represents the bottom-up method (Harish et al. 2022). However, the primary drawbacks of hybrid methods include high equipment costs and the requirement for highly toxic chemicals (Barhoum et al. 2022). Despite these challenges, the hybrid approach has resulted in the development of MOFs with structural features known to provide high capacity (Trickett et al. 2017).

Characterization techniques

Due to the rapid advancement of MOFs and their expanding array of applications, including drug delivery, gas and energy storage, smart sensor creation, and catalysis reactions, precise physicochemical and electrochemical characterizations are essential (Table 6). These analyzes play a crucial role in revealing the structural integrity, thermodynamic stability, and functional properties of MOFs (Abid et al. 2023). In recent years, significant progress has been made in the design and control of MOF properties, including the simplification and enhancement of synthetic and characterization methods, refinement of drug loading techniques, and implementation of postsynthetic modifications to tailor MOFs for medicinal purposes (Wang et al. 2023).

Table 6 Characterization techniques for nano-MOFs
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Standardized guidelines for synthetic characterizations (Hirschle et al. 2016) will enhance the robustness of data, increase lab-to-lab reproducibility, and increase the value of published information. This collective improvement will foster a more efficient and realistic evaluation of the technological and pharmaceutical potential of MOFs (Wang et al. 2023).

Tailoring nano-MOFs for drug delivery applications

MOFs have emerged as a notable class of diverse nanomaterials, including polymers, metals, metal oxides, and carbon nanostructures. MOFs are porous crystalline materials constructed from metal ions (or clusters) and organic linkers. Noteworthy attributes of MOFs include their ultrahigh porosity, substantial internal surface area, well-organized structure, and variety of functional groups (Masoudifar et al. 2022).

The structure of MOFs, and consequently, their physicochemical properties, can be readily adjusted through the deliberate selection of inorganic and organic components. This tunability facilitates the synthesis of MOFs with diverse morphologies, sizes, and shapes. Consequently, MOFs have found applications in various fields, including biomedicine (Yang and Yang 2020; Masoudifar et al. 2022). In the realm of biomedicine, MOFs can be customized with targeting molecules to facilitate active delivery or can be employed as responsive drug carriers, making them attractive candidates for DDSs (Wang et al. 2020; Masoudifar et al. 2022).

Surface functionalization

MOFs have become a promising platform for biomedical applications owing to their highly adjustable porosities, structural diversity, and multifunctionality (Chen et al. 2023). External surface modifications of MOFs impart new properties and functions, including hydrophilicity, colloidal stability, controlled payload release, specific targeted delivery, and biocompatibility. These features significantly enhance the effectiveness and applicability of MOFs in the diagnosis and treatment of various diseases (Chen et al. 2023).

Xie et al. (2022) successfully synthesized a multifunctional nanosized drug-delivery material, MIL-101(Fe)@FU@FA, with a uniform particle size of ~ 500 nm for targeted therapeutic applications. Folic acid molecules, which serve as targeting reagents, were covalently conjugated to the surface of 5-fluorouracil (5-FU)-loaded MIL-101(Fe)-NH2 nanoparticles. Cytotoxicity tests demonstrated that the blank nanoparticles were biocompatible within the concentration range of 0–50 μg/mL, maintaining a cell viability of greater than 90%. Compared to MIL-101(Fe)@FU, MIL-101(Fe)@FU@FA exhibited inhibitory effects on the proliferation of SMMC-7721 human hepatocellular carcinoma cells. Specifically, at a concentration of 64 μg/mL, the cell viabilities of MIL-101(Fe)@FU and MIL-101(Fe)@FU@FA were 13.5% and 11.8%, respectively. Metastasis and invasion experiments revealed that MIL-101(Fe)@FU@FA nanoparticles, in contrast to MIL-101(Fe)@FU, demonstrated notable antimetastatic effects on tumor cells. The comparison showed that MIL-101(Fe)@FU@FA inhibited cell migration (Fig. 6c) and invasion by ~ 42.2% and ~ 50%, respectively. In summary, the drug-loaded nanoparticles MIL-101(Fe)@FU@FA exhibited targeted therapeutic effects (Xie et al. 2022).

Size and shape modifications

Precision in shaping, sizing, and creating porosity is essential for the effective development and utilization of MOFs in particular contexts. Characteristics, such as the form, dimensions, porosity, and aggregation ratio, have a substantial impact on the ultimate properties of MOFs, and these properties can be adjusted by manipulating the synthesis parameters (Łuczak et al. 2023). The control of morphology is influenced by several factors, including pH, temperature, solvent, reagent concentration, component type, surfactants, ionic liquids, and methods such as microwaves and ultrasonication (Łuczak et al. 2023).

MIL-53(Al) was synthesized by Meshram and Sontakke (2021) at two distinct temperatures, 150 and 220 ℃, employing either water or dimethylformamide (DMF) as the solvent. In the hydrothermal synthesis, both temperature conditions yielded geometric structures with undefined shapes and smooth walls, exhibiting a minimal tendency for agglomeration. The particle size decreased from 1.402 to 0.713 μm with increasing temperature, while the surface area increased from 200.26 to 408.3 m2/g. Conversely, using DMF resulted in amorphous structures with a pronounced tendency to agglomerate. The size of these structures increased from 66.3 to 105.2 nm, and the surface area decreased from 1160.7 to 501.2 m2/g. The observed differences in morphology were ascribed to variations in the nucleation and crystal growth processes influenced by the solvent type. This discrepancy is attributed to the enhanced solubility of the linker in DMF compared to water, facilitating linker deprotonation and promoting formation (Meshram and Sontakke 2021).

Enhanced drug encapsulation and delivery

Improved drug loading capacities

MOFs are particularly well suited for biomedical applications due to their composition of highly porous inorganic materials and customizable organic groups. These features synergistically enhance the encapsulation of a wide range of substantial drugs, leading to improved drug loading capacity and controlled release at the intended site (Yadav et al. 2023b). The drug loading capacities of MOFs outperform those of other drug delivery vehicles, reaching values as high as 2 g of drug/g of empty MOF, equivalent to loading capacities exceeding 66 wt%. Furthermore, the release of drugs from MOFs can be gradual and controlled, preventing the release of therapeutically inactive bursts (Osterrieth and Fairen-Jimenez 2021).

Factors influencing the loading capacity

The loading method plays a crucial role in maximizing drug loading and achieving the desired release profiles in MOFs. Four prevalent methods for loading MOFs with drugs are one-pot synthesis, biomimetic mineralization, postsynthetic encapsulation, and surface loading. Surface loading, in particular, often yields lower drug loading than other methods and results in the rapid release of the drug from the MOF (Sun et al. 2018; Osterrieth and Fairen-Jimenez 2021). For instance, surface loading led to 4.9 wt% doxorubicin (DOX) loading (Vasconcelos et al. 2012), whereas one-pot loading in zeolitic-imidazole framework-8 composed of Zn2+ and 2-methylimidazole (ZIF-8) achieved loading levels of 14–20 wt% (Zheng et al. 2016).

Case studies on high-loading nano-MOFs

MOFs, an emerging type of crystalline porous material, have undergone extensive examination and application in diverse fields, such as catalysis and drug delivery. This is attributed to their outstanding porosity, substantial loading capacity, and ease with which their surfaces can be modified (Chen et al. 2021). Chen et al. (2021) employed an enhanced hydrothermal method to develop curcumin (Cur)-loaded γ-cyclodextrin (γ-CD)-MOFs (Cur-γ-CD-K-MOFs) and evaluated them for drug loading and stability. The findings revealed that, in comparison to γ-CD alone, γ-CD-MOFs displayed a 5.2-fold improvement in loading capacity (Fig. 7a) and enhanced physicochemical stability by ~ threefold (Chen et al. 2021). Cyclodextrins (CDs) are a group of naturally occurring cyclic oligosaccharides linked via α-1,4-glycosidic bonds. They come in three primary forms, namely, α, β, and γ-CDs, each with varying depths and diameters of internal cavities. This structural diversity enables them to efficiently immobilize various substances through host–guest interactions (Zong et al. 2022). Additionally, the oxygen-containing functional groups present in CDs serve as coordination sites for metal ions, facilitating the construction of CD MOFs. These CD MOFs offer several advantages, such as spacious cavities, well-defined pores, nontoxicity, and excellent biocompatibility, making them highly desirable for drug loading and release applications in therapeutic settings (Li et al. 2022; Yang et al. 2022; Zong et al. 2022). Li et al. (2021) synthesized a naringin-loaded β-CD-based MOF (CD-MOF) with dual-channel structures. Their formulation exhibited drug release following a zero-order kinetic model over a 30-day period, achieving a high entrapment efficiency of over 80%. Coculturing naringin/CD-MOF with an osteogenic cell line (MC3T3-E1 cells) revealed no adverse effects, suggesting the potential of CD-MOF as a carrier for zero-order DDSs.

Fig. 7
figure 7

Reproduced with permission from ref. (Tran and Lee). Copyright 2021 RSC

a Efficiency of encapsulation (EE) and loading capacity (LC) of curcumin (CUR) at concentrations ranging from 1 to 5 mg/mL in γ-cyclodextrin (γ-CD)-MOFs. As shown in the figure, by increasing the concentration of γ-CD-MOFs from 1 to 3 mg/mL, the EE and LC of CUR increased from 24.77 ± 1.92% and 19.83 ± 1.25 to 67.31 ± 2.25% and 30.97 ± 0.71%, respectively. When the concentration of CUR was consistently increased to 5 mg/mL, the EE and LC of CUR slightly decreased to 54.25 ± 3.49% and 17.98 ± 0.94%, respectively. This indicates that the continuous increase in the amount of γ-CD-MOF did not notably enhance the EE or LC. The optimum values were observed at a γ-CD-MOF concentration of 3 mg/mL. Reproduced with permission from ref. (Chen et al. 2021). Copyright 2021 Elsevier. b ICP‒OES measurements were employed to quantitatively analyze the uptake of the nanocomposites, specifically Mn3O4@PAA@ZIF-8 (3 mg/mL) and Mn3O4@PAA@ZIF-8/MTX (3 mg/mL), by the cell lines MCF-7, BT-474, and L929. As illustrated in the figure, the internalization of Mn3O4@PAA@ZIF-8 and Mn3O4@PAA@ZIF-8/MTX into cells exhibited a cell type-dependent pattern. The lowest and highest levels of cellular uptake were observed in L-929 and MCF-7 cells, respectively. Reproduced with permission from ref. (Foroushani et al. 2021). Copyright 2021 Elsevier. c The fluorescence intensity of Cy3-CpG released from isMOFs at various phosphate concentrations is depicted. The data are presented as the means ± SDs of triplicate samples. Reproduced with permission from ref. (Wang et al. 2017). Copyright 2017 ACS. d The release profiles of DOX from ZIF8-DOX and ZIF8-DOX@PAA in PBS at pH 7.4 and pH 4.0 at 37 °C.

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Foroushani et al. (2021) developed a composite nanomaterial system comprising manganese oxide (Mn3O4) nanoparticles for tumor diagnosis, polyacrylic acid (PAA) and ZIF-8 as pH-sensitive agents for drug delivery, and methotrexate (MTX) as both a tumor biomarker and therapeutic agent with dual functionality. The resulting composite, named Mn3O4@PAA@ZIF-8/MTX, was characterized to assess its drug loading efficiency and cellular uptake. The findings demonstrated an 80% drug loading efficiency for Mn3O4@PAA@ZIF-8/MTX. Cellular uptake evaluations revealed a significant increase in internalization by MCF-7 (~ 14.7-fold) and BT-474 (~ 6.4-fold) cancer cells compared to that of Mn3O4@PAA@ZIF-8 alone (Fig. 7b), underscoring the specificity and targeting effectiveness of Mn3O4@PAA@ZIF-8/MTX for cancer cells (Foroushani et al. 2021).

Controlled release mechanisms

The controlled release capability of MOFs has been demonstrated (Lawson et al. 2021). Certain frameworks exhibit inherent triggers for release, such as pH, ATP, and UV light, while others can be readily modified with components that regulate the release of therapeutic substances from their pores (Lawson et al. 2021). Additionally, the pores of MOFs can be engineered to either inhibit or enhance the diffusion of therapeutic cargo (Zheng et al. 2016; Lawson et al. 2021).

Manipulating the rate of MOF degradation in biological settings, and consequently, the drug release rate, is achievable by selecting alternative chemical components (Zheng et al. 2016; Lawson et al. 2021). The storage and release of therapeutic molecules are adjusted by controlling the structure and chemistry of the framework (Lawson et al. 2021). In many instances, this control was achieved by modifying the charge of the framework (Wang et al. 2017; Hidalgo et al. 2020). Wang et al. (2017) devised a formulation of immunostimulatory DNA-MOFs (isMOFs) by intrinsically coordinating CpG oligonucleotides onto biocompatible zirconium MOF nanoparticles. This construct was further fortified with the protective shell of a calcium phosphate exoskeleton. The researchers characterized the construct concerning CpG release at various phosphate buffer concentrations (pH 7). The release study results demonstrated a phosphate ion concentration-dependent release of CpG from the nanoparticles. Increasing the phosphate ion concentration led to greater release of the loaded CpG, as depicted in Fig. 7c (Wang et al. 2017).

Stimuli-responsive release

Regulating payload release from MOFs can be achieved through the use of gatekeepers. Stimuli, such as pH and glutathione, can induce the detachment of gatekeepers from MOFs (Sun and Davis 2021). Additionally, membrane gatekeepers have been investigated for MOF systems. Tran and Lee (2021) used PAA as a gatekeeper to synthesize a DOX-loaded ZIF8 nanostructure and subsequently assessed its effectiveness in regulating drug release. The findings demonstrated a pH-dependent release pattern, wherein ZIF8-DOX@PAA at pH 7.4 exhibited a low release rate of 24.7%, even after 100 h. In contrast, at pH 4.0, the nanostructure displayed four stages of release, with a significantly enhanced release rate reaching 84.7% at the final release stage after 30 h (Fig. 7d) (Tran and Lee 2021).

Stimulation of payload release can also be achieved by disrupting the MOF structure, weakening the metal ion-ligand interactions that maintain the system's integrity. This method has been applied to systems incorporating a drug (Paul and Dastidar 2016), a prodrug (Liu et al. 2017), or another therapeutic agent (such as photothermal, photodynamic, or imaging agents) as the organic ligand within the MOF structure. In such cases, the necessity for a gatekeeper is eliminated, as any stimulus that disrupts the coordination between the ligand and metal facilitates the release of the drug from the MOF (Sun and Davis 2021).

Sustained release profiles

Over the last three decades, MOFs have emerged as novel synthetic materials. These structures consist of organic ligands bridging metal ions, resulting in highly organized, porous, and three-dimensional (3D) crystalline structures (Shyngys et al. 2021). The pore size and aperture are notably smaller than those of polymeric structures, and their dimensions can be precisely manipulated (Shyngys et al. 2021). This precise control renders MOFs well suited for drug loading, enabling sustained or triggered release from nanoparticulate drug formulations or coatings (Wang et al. 2020). Consequently, the conventional understanding of "biomedical MOF applications" has focused primarily on their ability for drug delivery (Banerjee et al. 2020).

In the realm of sustained drug release, Sarkar et al. (2019) introduced a novel approach by developing a 3D cellulose-hydroxyapatite nanocomposite integrated with a dexamethasone-loaded MOF (HA/DMOF). This system served as a local DDS for bone tissue engineering. Through their evaluation, they demonstrated that HA/DMOF could sustainably release the loaded drug over a period of 4 weeks (Sarkar et al. 2019), offering promising prospects for controlled drug delivery in bone regeneration applications.

Similarly, Cai et al. (2022a) pioneered the development of CUR@IRMOF-16, a novel MOF-based nanoparticle system in which Zn-based IRMOF-16 served as a carrier for CUR. They meticulously assessed the release profile of the loaded drug and found that CUR@IRMOF-16, especially at a pH of 5.5, exhibited sustained release. Approximately 25.7% of the loaded drug was released after 240 h (Fig. 8a), demonstrating the potential of IRMOF-16 for continuously releasing CUR in a pH-dependent manner. This finding suggested that CUR@IRMOF-16 could be highly advantageous for tumor therapy (Cai et al. 2022a).

Fig. 8
figure 8

Reproduced with permission from ref. (Cai et al. 2022a). Copyright 2022 Elsevier. b The survival rates of mice following different treatment regimens. Notably, the survival rate in the SG@GR-ZIF-8 group reached 60% after 60 days, whereas the other treatment groups exhibited no survival. ***p < 0.001. Reproduced with permission from ref. (Hu et al. 2022). Copyright 2022 Elsevier. c i. Photoacoustic imaging of the tumor conducted both before and after in situ injection along with ii. In vitro photoacoustic images of ICG-CpG@MOF solutions at various concentrations (0, 0.5, 1, 2, 5, and 10 μg/mL). Reproduced with permission from ref. (Fan et al. 2021). Copyright 2021 Elsevier. d Viability of HeLa cells after incubation with various concentrations of Fe3O4@ZIF-8. The results indicate the significant biocompatibility of the Fe3O4@ZIF-8 nanoparticles, even at a high concentration (200 µg/mL), with a cell viability exceeding 80%. Reproduced with permission from ref. (Chen et al. 2018). Copyright 2018 RSC. e Viability of MCF-7 cells after incubation with GNRs-MSNs-MA for 24 or 48 h. The results demonstrate that, regardless of the incubation time (24 and 48 h) and even at high concentrations (400 µg/mL), these nanoparticles induced cell viabilities exceeding 80%. Reproduced with permission from ref. (Guo et al. 2021). Copyright 2021 Elsevier

a In vitro drug release curve of Cur@IRMOF-16 in a solution of PBS + Tween 80 (95:5 v/v) at pH 7.4 and 5.5 (n = 3, mean ± SD).

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Targeted drug delivery using nano-MOFs

In biomedicine, MOFs can be tailored with targeting molecules to serve as effective candidates for DDSs (Masoudifar et al. 2022). Techniques, such as grafting or layer-by-layer deposition, can modify the MOF surface and introduce targeted ligands capable of recognizing and binding to specific receptors or biomarkers on target cells, enabling customized administration or imaging applications (Gautam et al. 2023).

Postsynthetic modification (PSM) is a versatile method involving the introduction of targeted moieties into presynthesized MOFs. This can be achieved through covalent attachment, coordination chemistry, or surface functionalization techniques, allowing precise control over targeting ligands while preserving the integrity of the MOF structure (Chen and Zhao 2023).

Active targeting strategies

Active targeting strategies rely on the interaction between ligands and receptors, enabling selective accumulation at targeted sites and differentiation between diseased and healthy tissues. This approach, referred to as "smart drug delivery," involves the additional functionalization of drug-loaded nanocarriers with various ligands, such as antibodies, proteins, aptamers, peptides, and small molecules, achieved through chemical conjugation or physical adsorption (Masoudifar et al. 2022).

Hu et al. (2022) integrated sorafenib (Sor) and glucose oxidase (GOx) into an N-acetyl-galactosamine (GalNAc)-modified zeolitic imidazolate framework (ZIF-8), termed SG@GR-ZIF-8, for targeted bimodal therapies against hepatocellular carcinoma (HCC) involving chemotherapy and starvation therapy. Hepatic delivery of SG@GR-ZIF was facilitated by specific recognition of GalNAc residues with asialoglycoprotein on the liver cell surface. The results showed significant anti-metastatic HCC activity against C5WN1 cells, reducing cell viability to 6.7%. In a subcutaneous C5WN1-tumor-bearing mouse model, SG@GR-ZIF exhibited potent synergistic antitumour activity, with an 89% tumor inhibition rate and prolonged survival. After 60 days, the survival rate of the plants in the SG@GR-ZIF-8 group was 60%, while that of the other groups reached zero (Fig. 8b). This therapeutic strategy targeting the energy supply combined with first-line treatment holds promise for future metastatic HCC treatment (Hu et al. 2022).

Passive targeting via enhanced permeability and retention

Efficient drug accumulation at target sites is crucial for treating diseases, such as solid tumors, where significant adverse effects stem from cytotoxic drug distribution in normal tissues (Farooq et al. 2019). This targeting can occur passively through the enhanced permeability and retention (EPR) effect or actively by targeting ligands on nanocarriers (Masoudifar et al. 2022). The EPR effect capitalizes on the leakiness of tumor blood vessels and disordered endothelium, allowing for increased accumulation of macromolecules in tumor tissues compared to normal tissues (Kanungo et al. 2024). Factors, such as tumor biology, vasculature, and drug properties such as shape, charge, and size, can influence the efficiency of passive targeting (Masoudifar et al. 2022).

Nanoscale MOFs, a novel category of hybrid materials composed of metal attachment sites and bridging ligands, have emerged as promising platforms for advancing cancer diagnosis and therapy. Their adjustable size, customizable surface, favourable biocompatibility, high agent loading capacity, and, notably, ability to selectively accumulate in tumors via the EPR effect make them particularly attractive (Zhao et al. 2022). In a study by Fan et al. (2021), multimodal imaging-guided synergistic cancer photoimmunotherapy was developed using a specific MOF (MIL101-NH2) as the core carrier. This MOF was equipped with both photoacoustic and fluorescent signal donors (indocyanine green, ICG) and immune adjuvants (CpG) and was named ICG-CpG@MOF. Subsequent evaluation of the efficacy of the formulation in vivo in a tumor-bearing mouse model revealed a photoacoustic signal at the tumor site 6 h after tail vein injection (Fig. 8c). Strong photoacoustic signals were observed postinjection, and the relationship between the signal strength and concentration is shown in Fig. 8c. These findings indicate the effective passive tumor-targeting ability of ICG-CpG@MOF, likely attributed to the EPR effect at tumor sites and the size of the MOF (Fan et al. 2021).

Biocompatibility and toxicity considerations

Biocompatibility of nanoMOFs

When employing MOFs in DDSs, careful consideration of their biocompatibility and toxicity is imperative, as they are directly linked to MOF compositions (Nel et al. 2015). It is essential for both linkers and metals to be nontoxic (He et al. 2021b).

Due to the weak coordinative bonds in MOF structures, they are susceptible to degradation in biological environments, resulting in the release of their constituent ligands. This leads to exceptional biodegradability and biocompatibility once their intended purpose is fulfilled (He et al. 2021b).

In vitro biocompatibility studies

To evaluate the toxicity of substances to living organisms, the initial stage involves conducting both in vitro and in vivo studies. Each test offers complementary insights, making it essential to carry out both approaches. In vitro studies allow for a detailed examination of the cytotoxic effects on specific mammalian cells, such as target-organ cells, without raising ethical concerns (Wiśniewska et al. 2023). Consequently, various studies (Chen et al. 2018; Guo et al. 2021) have assessed the in vitro biocompatibility of MOFs.

Chen et al. (2018) synthesized core–shell structures of Fe3O4@ZIF-8 nanoparticles and assessed their toxicity to human cervical cancer HeLa cells. The findings revealed that even at a concentration of up to 200 mg/L, the Fe3O4@ZIF-8 nanoparticles induced ~ 80% cell viability, suggesting the favourable biocompatibility of the synthesized Fe3O4@ZIF-8 composites (Fig. 8d) (Chen et al. 2018).

In a separate investigation, Guo et al. (2021) created a multifunctional nanocarrier by depositing a MOF onto core–shell gold nanorod-mesoporous silica nanoparticles (GNRs-MSNs). Following the additional modification of GNRs-MSNs-MOF with hyaluronic acid, the resulting nanoparticles, termed GNRs-MSNs-MA, were evaluated for cytotoxicity using a CCK-8 assay. After 24 h of incubation with the nanoparticles, the viability of human breast cancer MCF-7 cells remained above 80%, even at a high concentration of 400 μg/mL (Fig. 8e). Furthermore, no significant decrease in cell viability was observed after prolonged incubation for 48 h, indicating the outstanding biocompatibility of the GNRs-MSNs-MA nanoparticles (Guo et al. 2021).

In vivo biocompatibility assessment

Evaluating the in vivo toxicity of materials provides insights into their absorption, distribution, and behavior throughout the organism, offering a more comprehensive perspective than focusing solely on the concentration within single cells. This approach not only aids in detecting unforeseen side effects but also allows for the assessment of potential risks (Jain et al. 2018). Despite optimistic outlooks, the advancement of MOFs in biomedicine is contingent upon conducting thorough toxicity studies (Wiśniewska et al. 2023).

Cheng et al. (2024) developed a collaborative composite, denoted P-F-HKUST-1, by combining a thermoresponsive hydrogel (PPCN) with folic acid-modified copper-based MOFs (F-HKUST-1) for hindlimb ischemia therapy. The in vivo biocompatibility of the formulations was evaluated by monitoring changes in body weight. The results demonstrated that PPCN, F-HKUST-1, and P-F-HKUST-1 did not induce noticeable weight loss, suggesting their biocompatibility at the administered doses (P-F-HKUST-1 at 6.4 μg/mL copper) (Cheng et al. 2024).

Assessing and mitigating potential toxicity

The biocompatibility of MOFs is significantly influenced by their chemistry, particle size, morphology, and aggregation, as noted by Wiśniewska et al. (Wiśniewska et al. 2023). Therefore, careful design and manipulation of these factors can effectively reduce the inherent harmfulness of these structures, thereby enhancing their suitability for biomedical uses. However, it is important to acknowledge that even a meticulously planned model with specific properties cannot ensure complete safety for living organisms. To address MOF toxicity, various strategies, such as green chemistry and surface modifications, are employed, irrespective of the physical and chemical characteristics of the MOF (Wiśniewska et al. 2023).

Green chemistry

Adopting eco-friendly ligands, linkers, and solvents to alter MOF chemistry offers a promising avenue for reducing toxicity. However, this tactic presents hurdles, as substituting it with natural or green alternatives may compromise the performance and functionality of MOFs. Nonetheless, in recent years, considerable endeavors have focused on crafting, synthesizing, and assessing the effectiveness of eco-friendly MOFs for biomedical uses (Abuçafy et al. 2018; Grape et al. 2020).

Grape et al. (2020) synthesized a bioinspired microporous MOF using ellagic acid, a common natural antioxidant and polyphenol building unit. The resulting formulation, SU-101, was evaluated for its biocompatibility with a promyelocytic cell line (HL-60). The results indicated a minimal cytotoxicity profile even after 24 h of cell contact, with an 80% maximum inhibitory concentration (IC80) observed at 1000 μg/mL. Remarkably, SU-101 exhibited low cytotoxicity even at very high concentrations, reaching up to 1200 μg/mL (Grape et al. 2020).

Surface modifications

In addition to the use of green precursors and/or solvents, surface modifications are crucial for mitigating the toxicity of MOFs. Surface properties dictate the interactions between the framework and the biological environment, and appropriately modifying them can restrict direct contact between MOFs and cell surfaces (Li et al. 2020b). Various types of modifications have proven beneficial for MOF biosafety, including coating with biomolecules, surface modification through covalent bonding, and pressure-induced amorphization (Wiśniewska et al. 2023).

Jiang et al. (2021) engineered amorphous ZIF-8 (aZIF-8) with a high loading of 5-FU through pressure-induced amorphization. Various formulations of aZIF-8 (ZIF-8–0.3 GPa, ZIF-8–0.6 GPa, and ZIF-8–0.9 GPa), in comparison to its crystalline counterpart (ZIF-8), were characterized by their crystallographic structure, chemical composition, physical properties, size, morphology, cell viability, in vivo toxicity, and therapeutic effects. These findings indicated that pressure-induced amorphization of ZIF-8 enhanced its in vitro and in vivo biocompatibility. XRD analysis confirmed that amorphization was achieved by applying different amounts of pressure (Fig. 9a).

Fig. 9
figure 9

ZIF-8 underwent characterization before and after amorphization using various techniques: a XRD analysis, b FT-IR analysis, c TEM imaging, and d DLS analysis comparing ZIF-8 (preamorphization) with ZIF-8–0.3 GPa, ZIF-8–0.6 GPa, and ZIF-8–0.9GPa (postamorphization). Additionally, e the viability of ECA-109 cells was assessed 24 h after exposure to ZIF-8 (pre- and postamorphization). f Mouse survival rates were evaluated one day after inoculation with varying concentrations of ZIF-8 (pre- and postamorphization) (12.5–100 mg/kg). g Images of tumor-bearing mice were captured on day 14 posttreatment with PBS (placebo), ZIF-8 loaded with the anticancer drug 5-FU, and amorphous ZIF-8 loaded with 5-FU. Finally, h the relative tumor volume over time and i the mouse survival rate over time were monitored. These data were reproduced with permission from ref (Jiang et al. 2021), Copyright 2021 Elsevier

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Furthermore, amorphous ZIF-8 (a-ZIF-8) particles exhibited a slight increase in size and irregularity while maintaining their chemical structure (Fig. 9b–d). The results from the ECA-109 cell viability assay (Fig. 9e) revealed a markedly reduced toxicity (decreased by 81.4%) of ZIF-8 subjected to pressures of at least 0.6 megapascal compared to its crystalline form. This decrease in toxicity correlated with a decrease in the release of Zn2+ and the production of reactive oxygen species (ROS), which are known factors contributing to nanoparticle toxicity. Similar trends were observed in vivo; for instance, the administration of 100 mg/kg of crystalline ZIF-8 resulted in mortality in all mice, whereas a-ZIF-8 had no impact on survival rates (Fig. 9f). Notably, this pattern persisted when the MOF was loaded with the drug (5-FU). As depicted in Fig. 9g–i, treatment with 12 mg/kg a-ZIF-8 effectively decreased tumor volume, facilitating mouse recovery without adversely affecting any organs. Consequently, tumor recovery could not be achieved with untreated ZIF-8 (Jiang et al. 2021).

Current clinical trials

While numerous studies, including extensive publications and patents (Hidalgo et al. 2020; Ke et al. 2020; Li et al. 2020a; Sun and Davis 2021a), have supported the potential of MOFs for biomedical applications, transitioning to clinical trials requires cautious consideration. In vivo experiments on mammals, particularly larger animals and humans, are limited. Success in laboratory or small animal studies does not guarantee safety and efficacy in human applications (Wiśniewska et al. 2023). It is important to emphasize that clinical trials are not focused solely on assessing toxicity; their primary goal is to confirm the safety and effectiveness of a medical strategy.

Conducting trials on humans involves significant responsibility, and initiating the clinical phase should only occur after a systematic and thorough research process that nearly guarantees safety. However, even with extensive research, there is always a degree of risk, as unpredictable side effects may arise due to variations in individual immune responses (Wiśniewska et al. 2023). Indeed, the journey from initial research to clinical trials is a complex and lengthy process. Despite the challenges and the distant nature of the goal, it is crucial not to discontinue further research. Patience is a key virtue, especially as the transition to the clinical phase unfolds (Wiśniewska et al. 2023). The clinical phase, while running relatively smoothly, is a time-consuming endeavor, typically spanning from a few years to several decades. This extended timeline is attributed, in part, to the necessity of obtaining numerous regulatory and ethical approvals, recruiting diverse groups of volunteers (from various countries and age groups), and the protracted duration of the treatment process (Wiśniewska et al. 2023). Despite being extensively featured in numerous publications and possessing ~ 90,000 known structures (Moosavi et al. 2020), only two materials have progressed to human trials—RiMO-401 in phase I (NCT06182579) and RiMO-301 in phase II (NCT0583872910) (Forgan 2024). RiMO-301, a hafnium-based MOF, has shown promise in enhancing radiotherapy and checkpoint blockade immunotherapy in preclinical models without exhibiting systemic toxicity (Koshy et al. 2023). However, some experts have raised concerns regarding the slower-than-expected pace of clinical translation, citing various challenges.

One significant issue is the biocompatibility of transition metals used in the framework, which has been highlighted as a potential barrier (Tyagi et al. 2023). Additionally, the diverse range of structures achievable through reticular chemistry in MOFs complicates toxicity prediction based on composition. Factors, such as size, morphology (anisotropic versus isotropic particles), and formulation, must be individually assessed. Unfortunately, comprehensive data on the selection of a specific MOF for a particular clinical application are lacking. Moreover, the translation of MOFs is hindered by their instability in biological fluids, such as serum and blood. The metal centers in MOFs are kinetically labile and susceptible to stripping by endogenous proteins (e.g., albumin) and biological anions (phosphates), leading to premature drug release, structural degradation, and diminished efficacy (Tyagi et al. 2023).

Challenges and future directions

While MOFs offer exceptional properties that render them promising platforms for disease diagnosis and drug delivery, challenges still abound in this domain. There are few studies (Zhou et al. 2021; Abd Al-jabbar et al. 2022) addressing the biological applications of these materials (Al Sharabati et al. 2022). Key characteristics, such as degradability, blood circulation half-life, stability, and selectivity, are crucial for MOFs to function effectively in the body. The efficiency of controlled release, imaging, and sensing ultimately depends on these diverse characteristics (Al Sharabati et al. 2022). Addressing these challenges is essential for advancing the practical application of MOFs in biomedical contexts.

To date, there has not been a comprehensive comparative analysis of MOF efficacy, resulting in a limited understanding of their suitability for biological applications (Zhang et al. 2020). Moreover, the synthesis of stable and uniformly dispersed MOF formulations poses a significant challenge due to their tendency to degrade. Stability concerns also arise during surface modification, while initial outcomes may appear promising, there is a crucial need for thorough assessment of both the surface modification process and the ultimate stealth properties of engineered nanoparticles (Horcajada et al. 2012). Tackling these hurdles is vital for advancing the reliable and efficacious utilization of MOFs in biological contexts.

Furthermore, it is crucial to prioritize the exploration of MOF biocompatibility and toxicology. Currently, there is a notable dearth of information concerning the in vivo toxicity, pharmacokinetics, and biodistribution of diverse novel MOFs. These aspects are pivotal for conducting preclinical assessments of the biocompatibility of emerging materials. Although several in vitro toxicity studies have been conducted on various cell lines, comparing their outcomes presents challenges (Sun et al. 2020). Additionally, attaining a comprehensive understanding of the reaction and metabolism mechanisms is essential for optimizing MOF performance prior to potential clinical use (Zhang et al. 2020). To advance MOF research, consistent synthesis techniques and reproducible properties across different research entities are imperative. The establishment of standardized protocols, characterization methods, and reporting criteria will bolster the comparability and reliability of study results (Gautam et al. 2023). Such standardization is crucial for advancing the field and ensuring the safe and efficacious utilization of MOFs in biomedical applications.

Beyond the synthesis step, it is crucial to consider the fate of MOFs when they are employed in biological systems and after their release into the environment postuse. Therefore, it is essential to thoroughly assess methods that ensure the safe and environmentally friendly use and disposal of these materials in biomedical systems. The complete environmental impact of MOFs, spanning from processing to final disposal, should be carefully considered in the analysis (Far et al. 2023).

The future of MOFs holds significant promise for both clinical and industrial applications. MOFs can be customized to fulfil the specific needs of individual patients, facilitating personalized drug delivery and treatment plans (Gautam et al. 2023). The realm of personalized medicine could witness a revolution with the emergence of patient-specific MOFs engineered to respond to distinct biomarkers or disease conditions. Theragnostic platforms, which integrate diagnostic and therapeutic functionalities into MOFs, may soon become a reality. These technologies offer personalized therapy monitoring and enhanced patient outcomes by simultaneously diagnosing diseases and administering tailored medications (Gautam et al. 2023). The adaptability and adjustability of MOFs position them as promising contenders for advancing precision medicine and refining treatment approaches tailored to individual patients.

Conclusion

In conclusion, the exploration of nano-MOFs for next-generation drug delivery has revealed possibilities and challenges, marking a significant stride in the quest for innovative biomedical solutions. Throughout this discourse, key findings underscore the unique attributes of nano-MOFs that make them promising candidates for use in DDSs. Their controlled release mechanisms, stimuli-responsive behaviors, and sustained release profiles provide a nuanced toolkit for tailoring drug delivery to specific therapeutic needs.

The versatility of nano-MOFs is particularly noteworthy, as evidenced by their integration into targeted DDSs. Active targeting strategies, facilitated by grafting or layer-by-layer deposition, offer a personalized approach that holds immense potential for the treatment of various diseases. The demonstrated success of nano-MOFs, such as SG@GR-ZIF-8, in liver cancer therapy exemplifies the transformative impact that these materials can have on clinical outcomes.

Biocompatibility and toxicity considerations have emerged as pivotal facets in assessing the translational potential of nano-MOFs. While in vitro studies indicate promising biocompatibility, a comprehensive understanding of in vivo toxicity, pharmacokinetics, and biodistribution is imperative for holistic evaluation. Green chemistry approaches and surface modifications present viable strategies to mitigate potential toxicity, emphasizing the need for meticulous design and manipulation of nanoMOF properties.

As we reflect on the impact of nano-MOFs on next-generation drug delivery, challenges abound, ranging from issues of stability to the imperative for standardized protocols. The absence of a systematic comparison and limited studies in biological applications accentuate the need for continued research and collaborative efforts. Despite these challenges, the future of nano-MOFs holds immense promise.

Nano-MOFs could revolutionize drug delivery, offering avenues for personalized medicine through tailored formulations and theranostic platforms. The advent of patient-specific nano-MOFs designed to respond to unique biomarkers ushers in the era of precision medicine. Therapeutic strategies that seamlessly integrate diagnostics and treatment pave the way for enhanced patient outcomes and therapy monitoring.

In the grand tapestry of biomedical advancements, nano-MOFs have emerged as a crucial thread, weaving together innovations, challenges, and the potential for transformative impact. The journey from the laboratory to clinical trials is complex, but the potential benefits for patients and the field of medicine have advanced. With cautious optimism and dedicated research, nano-MOFs may very well shape the landscape of next-generation drug delivery, heralding a new era in personalized and effective therapeutic interventions.