Introduction

Curcumin, a natural polyphenolic compound derived from the rhizomes of Curcuma longa, exhibits a wide spectrum of pharmacological activities, including potent anti-inflammatory, antioxidant, antitumor, and neuroprotective effects, and thus holds great promise in the treatment of cancer, neurodegenerative diseases, and metabolic disorders1,2,3,4. However, its poor aqueous solubility, chemical instability, and rapid metabolic clearance result in extremely low systemic bioavailability, posing a major barrier to its clinical translation5,6,7,8. Clinical investigations have shown that even at oral doses as high as 12 g per day, plasma concentrations of unmodified curcumin remain at nanomolar levels, with most of the drug excreted in its unmetabolized form. This paradox of “high pharmacological activity but poor bioavailability” severely limits curcumin’s therapeutic potential. To overcome these challenges, extensive formulation strategies have been explored, including liposomal encapsulation, polymeric micelles, solid lipid nanoparticles, and nanocrystal formulations, all aiming to improve solubility, stability, and in vivo retention9,10,11,12,13. Despite these advances, the rational design of carrier systems capable of achieving high loading efficiency, controlled release, and molecular stability remains a key research frontier in curcumin delivery.

Metal-organic frameworks (MOFs) have emerged as highly versatile materials for drug delivery, owing to their tunable pore sizes, ultrahigh surface areas, adjustable chemical functionality, and intrinsic biocompatibility14,15. Among them, the MOF-74 (CPO-27) series has attracted particular attention because of its one-dimensional hexagonal channels, high density of open metal sites, and remarkable chemical stability16. MOF-74 structures are constructed via the coordination of 2,5-dihydroxyterephthalic acid (DOBDC) linkers with divalent metal ions such as Mg2+, Zn2+, Ni2+, Mn2+, or Co2+. These open metal nodes can interact with guest molecules through coordination bonding, electrostatic interactions, and van der Waals forces, substantially enhancing the framework’s drug loading capacity17,18. Consequently, MOF-based carriers offer distinct advantages, including high payload capacity, sustained and stimuli-responsive release, and potential for targeted delivery19,20.

Recent studies have demonstrated that the metal node identity in MOF-74 crucially modulates host-guest interactions by altering the framework’s charge distribution, Lewis acidity, and pore microenvironment21,22,23,24,25. For instance, MOF-74 matrices effectively protect encapsulated drugs from degradation, exhibit pH-responsive release profiles, and display selective release behavior under tumor-mimicking microenvironments26. Lawson et al. utilized Mg-MOF-74 for the co-delivery of ibuprofen and curcumin, establishing a dual-drug delivery paradigm in which curcumin loading beyond 10% notably decreased ibuprofen encapsulation efficiency27. Similarly, tuning the Mg/Zn ratio in hybrid MOF-74 systems allows precise regulation of curcumin release kinetics, increasing the Mg fraction enhances both the cumulative release amount and rate, highlighting the pivotal role of metal nodes in controlled release28. Furthermore, Zn-MOF-74’s gradual decomposition during drug release reduces potential in vivo invasiveness, suggesting favorable biodegradability and biocompatibility29. A comparative investigation across the M-MOF-74 family (M = Mg, Ni, Zn, Co) also revealed that metal centers with higher aqueous solubility promote faster release kinetics, demonstrating a clear correlation between metal node characteristics and drug diffusion behavior30.

Building on these findings, this work employs a combined Density Functional Theory (DFT) and Molecular Dynamics (MD) framework to systematically investigate the adsorption and diffusion behavior of curcumin within five representative M-MOF-74 variants (Mg, Zn, Ni, Mn, Co). DFT analyses of curcumin’s electronic and quantum chemical properties are integrated with 100 ps MD simulations to elucidate molecular diffusion dynamics, saturation adsorption capacity, preferred binding sites, and adsorption thermodynamics. This study aims to uncover, at the atomic and electronic levels, the structure-activity relationship governing the interplay between metal node characteristics and curcumin loading performance. The resulting insights may guide the rational design of high-capacity, controlled-release MOF-based curcumin delivery systems, addressing one of the key bottlenecks in curcumin’s clinical translation.

Materials and methods

DFT calculations for Curcumin

Quantum chemical properties of curcumin were evaluated by DFT. Molecular geometries were fully optimized using the B3LYP31 functional with empirical dispersion correction (B3LYP-D3) and the 6-31G (d, p) basis set (Gaussian 09, Linux). Frequency analyses confirmed stationary points as minima (no imaginary frequencies). Single-point energies were computed on the optimized geometries using the same functional and basis set. Wavefunction analyses, including HOMO/LUMO distributions, molecular electrostatic potential (ESP), interaction region indicator (IRI) and reduced density gradient (RDG) analyses were performed with Multiwfn v3.8 to identify reactive sites and noncovalent interaction regions.

Molecular dynamics simulations

Model construction

Crystal structures of M-MOF-74 (M = Mg, Zn, Ni, Mn, Co) were retrieved from the Cambridge Crystallographic Data Centre (CCDC). All structures adopt the hexagonal MOF-74 topology (space group R-3, No. 148) with one-dimensional hexagonal channels. When required to avoid spurious interactions from periodic images and to preserve channel continuity, supercells of up to 2 × 2 × 8 were constructed.

Monte carlo-based molecular dynamics simulation

Simulations were performed with Materials Studio 2023 (MS 2023) using the COMPASS III force field. To obtain saturated adsorption capacities and adsorption kinetics for curcumin in each M-MOF-74 variant, we employed a two-stage simulation protocol combining Monte Carlo placement and molecular dynamics sampling:

In the first stage of the pre-equilibrium simulation, the system was first subjected to 100 ps of temperature and pressure equilibration, with the temperature set to 298.15 K and the pressure set to 101.325 kPa, ensuring that the system reached a thermodynamic stable state under these conditions. Subsequently, the simulation entered the energy convergence stage, performing a 1000 ps simulation to ensure the system’s energy stabilized. The main objective of this stage was to bring the system to a steady state that closely resembles actual experimental conditions, providing a suitable initial state for the subsequent equilibrium simulation.

The second stage of the equilibrium simulation lasted for 20,000 ps, resulting in a total of 1 × 108 steps. During this stage, long-duration simulations ensured that the system thoroughly explored various possible microscopic structures and interaction patterns, yielding accurate data on the curcumin molecule adsorption capacity. This simulation phase provided reliable dynamic data support for evaluating the influence of different metal nodes on the adsorption characteristics of curcumin.

In addition, to further validate the applicability and accuracy of the COMPASS III force field in open metal systems, the study also performed a force field transferability test. We selected clusters of the five MOF-74 metal nodes and optimized their geometric structures based on both the PBE-GGA functional and the COMPASS III force field. The test results (Table 1) showed that no significant differences were observed in the optimization results, regardless of the force field used, thereby confirming the reliability and applicability of the COMPASS III force field when handling open metal node systems.

Table 1 Calculation of force field transferability.
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Calculation of mean square displacement and diffusion coefficient

In this study, the Mean Square Displacement (MSD) method is used to calculate the diffusion coefficient of curcumin molecules, thereby quantifying their diffusion behavior within the MOF-74 channels. The mean square displacement refers to the degree of deviation of a particle’s position relative to its initial position. The specific calculation formula is as follows:

$$\:MSD\left(t\right)\:=\:<{\left|r\left(t\right)-r\left(0\right)\right|}^{2}>\:=\:\frac{1}{N}\:\sum\:_{i=1}^{n}<{\left|{r}_{i}\left(t\right)-{r}_{i}\left(0\right)\right|}^{2}>$$

In the system, {r}_i(t) is the position vector of the center of mass of the i-th curcumin molecule at time t, ri(0) is the initial position vector, N is the total number of curcumin molecules in the system, and < \dots > denotes the ensemble avera.

According to the Einstein relation, the self-diffusion coefficient D of a three-dimensional isotropic diffusion system can be obtained from the slope of the linear region of the MSD curve:

$$\:D=\:\frac{1}{6}\:\underset{\Delta\:t\to\:\infty\:}{\text{lim}}\:\frac{dMSD}{d\Delta\:t}$$

where the coefficient 6 corresponds to the dimensionality of three-dimensional space.

The MSD data collection and processing involve extracting the last 500 ps from the trajectory of the NVT simulation production phase, recording the centroid coordinates of the curcumin molecules every 10 ps. To exclude the influence of the initial ballistic regime, the linear region of the MSD curve from 10 to 100 ps is selected for least-squares linear fitting. The slope K of the fitted line is related to the diffusion coefficient by D = k/6. To ensure statistical reliability, the diffusion coefficients calculated from three independent repeated simulations are averaged, and their standard deviation is reported. The fitting process requires a correlation coefficient R2 > 0.99 to ensure the validity of the linear relationship.

Differential analysis of adsorption mechanisms

Materials Studio 2023 was utilized for theoretical analyses. Geometry optimization and energy calculation were executed using CASTEP module using generalized gradient approximation (GGA) framework with Perdew-Burke-Ernzerhof (PBE) functional. The valence wavefunctionswere expanded by plane waves with a cutoff energy of 400 eV. Thecalculations were carried out for all structures using a 2 × 1 × 1 k-pointgrid. DFT-D dispersion correction was realized by TS method to account for van der Waals interaction. To describe realistic magnetic behavior and electronic correlation effects, spin-polarized settings were implemented for Ni, Mn, and Co-based MOFs, with a U value of 2.5 applied. The convergence tolerance was set as 1.0 × 10− 5 eV/atom for energy, 3.0 × 10− 2 eV/Å for force, 5.0 × 10− 2 GPa for stress and 1.0 × 10− 3 Å for displacement.

The calculation formula for adsorption energy is as follows:

$${\rm E_{ads}=E_{total} - E_{Curcumin} - E_{MOF}}$$

where E total, E Curcumin and E MOF are the energies of total system, Curcumin and the MOF, respectively.

Results and discussion

Electronic structure characteristics and adsorption mechanism prediction of Curcumin

Figure 1 systematically presents the quantum chemical properties of curcumin, including the highest occupied molecular orbital (HOMO), and lowest unoccupied molecular orbital (LUMO) (Fig. 1A), Interaction Region Indicator (IRI) and Reduced Density Gradient (RDG) (Fig. 1B, C), electrostatic potential (ESP) (Fig. 1D), and localized orbital locator function (LOL) (Fig. 1E). The electronic structure characteristics revealed by density functional theory (DFT) calculations provide theoretical foundations for elucidating adsorption differences between curcumin and various metal node MOF-74 variants.

Fig. 1
figure 1

Electronic structure characterization of curcumin molecule. (A) Frontier molecular orbitals (HOMO and LUMO); (B) Interaction Region Indicator (IRI); (C) Reduced Density Gradient (RDG); (D) Molecular Electrostatic Potential (ESP); (E) Localized Orbital Locator (LOL).

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Fig. 2
figure 2

Crystal structures and pore characteristics of five MOF-74 variants showing one-dimensional hexagonal channels with different metal nodes (Mg, Zn, Ni, Mn, Co).

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Frontier orbital analysis reveals that HOMO (−0.25 eV) is primarily localized on the 4-hydroxy-3-methoxyphenyl unit32, serving as an electron donor capable of coordinating with MOF-74 metal nodes (e.g., Zn2+, Mg2+) through phenolic hydroxyl and methoxy oxygen atoms. The LUMO (−0.07 eV) is delocalized over the heptadienone chain, suggesting its potential role as an electron acceptor that can engage in metal d-orbital back-donation (e.g., d5 electrons from Mn2+) or π-π stacking with the aromatic rings of the MOF-74 ligand.

Weak interaction analysis (IRI/RDG) further reveal the presence of intramolecular O-H···O-CH3 hydrogen bonds and van der Waals interaction networks along the heptene backbone33,34. These weak interactions significantly influence the conformational entropy changes within confined channels. For instance, in smaller-pore Zn-MOF-74 (15.2 Å), spatial constraints enhance van der Waals forces interaction, thereby reducing adsorption entropy. Additionally, π-π stacking between MOF-74’s 2,5-dihydroxyterephthalic acid ligands and curcumin’s heptadiene chain, while metal open sites (e.g., Zn-O clusters) can form hydrogen bonds with phenolic hydroxyl groups to cooperative stabilization of the adsorption process.

Electrostatic potential (ESP) and localized orbital (LOL) analyses further confirm key active sites35,36. The β-diketone group of Curcumin displays strong positive electrostatic potential (ESP), favoring electrostatic attraction with negatively charged coordination oxygen in MOF-74 (e.g., Zn-O−). Conversely, the negative charged phenoxy groups preferentially interact with high charge density metal cations (e.g., Mg2+). LOL mapping clearly identifies high electron localization characteristics of carbonyl oxygen (C = O), predicting its role as the primary coordination site forming Mn-O or Zn-O bonds. The bond lengths and coordination geometries are modulated by the metal d-orbital properties, such as Jahn-Teller distortion in Mn2+ systems.

Structural parameters and channel properties of MOF-74

All five MOF-74 variants (Mg/Zn/Ni/Mn/Co) crystallize in the hexagonal system (space group R-3, No. 148), with unit cell parameters summarized in Table 1. Channel diameter differences directly impact drug loading performance. Among them, Co-MOF-74 exhibits the largest pore size (15.734 Å), followed by Mn-MOF (15.399 Å), while Mg-, Zn-, and Ni-MOF possess similar pore sizes (approximately 15.2 Å). As illustrated in Figure. 2, larger pore sizes potentially enhance drug loading capacity and diffusion rates by reducing steric hindrance and increasing the availability of adsorption sites.

Adsorption kinetics and metal node effects

Comprehensive analysis of curcumin adsorption with five MOF-74 nanochannels reveals distinct kinetic and thermodynamic behaviors depending on the metal node.

As shown in Fig. 3, adsorption kinetics display dependence. Co-MOF-74 achieves saturation adsorption in the shortest steps (3 × 106 steps) with a loading capacity of 58 molecules, demonstrating its kinetic superiority. Mn-MOF-74 exhibits the highest saturation adsorption capacity (59 molecules), exhibiting strong thermodynamically preferential characteristics. In contrast, Ni-MOF-74 presents the slowest adsorption kinetics (saturation at 9 × 106 steps) with the lowest capacity (57 molecules). Although Zn-MOF-74 does not achieve the highest capacity or the fastest rate, it demonstrates excellent adsorption efficiency, achieving substantial loading with relatively rapid adsorption time.

Fig. 3
figure 3

Adsorption kinetics and spatial distribution of curcumin in M-MOF-74 materials. (a) Time-dependent adsorption profiles showing the evolution of curcumin uptake for Co-, Mg-, Mn-, Ni-, and Zn-MOF-74 materials. All materials exhibit rapid initial adsorption followed by plateau behavior, indicating saturation. (b) Energy-density distribution profiles revealing the interaction strength between curcumin molecules and different metal centers. The distribution breadth and peak position reflect metal-specific binding affinities. (c) Three-dimensional visualization of curcumin spatial distribution within saturated MOF pores, where higher density (darker red regions) indicates preferential binding sites near metal nodes. Key finding: Metal identity significantly influences both the adsorption kinetics and the spatial localization of curcumin, with transition metals (Co, Ni) showing stronger and more localized interactions compared to Mg and Zn variants.

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The Mean Square Displacement (MSD) further shows curcumin diffusion behavior with different MOFs. The slope of the curves in Fig. 4 follows the trend: Mg-MOF < Mn-MOF < Co-MOF < Ni-MOF < Zn-MOF. The highest diffusion coefficient in Zn-MOF indicates the weakest adsorption, thus leading to the most significant diffusion within the pores. In contrast, the lowest diffusion coefficient observed in Mg-MOF, which suggests stronger adsorption interactions that restrict molecular motion.

Fig. 4
figure 4

MSD analysis of curcumin adsorption by five MOF materials.

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Thermodynamic analysis of adsorption based on Monte Carlo simulation

Monte Carlo simulations were employed to evaluate the thermodynamic parameters governing curcumin adsorption on five MOF-74 variants (Fig. 5). The calculated energy components include total energy, average total energy, van der Waals energy, electrostatic energy, and intramolecular energy at different simulation steps.

Fig. 5
figure 5

Energy decomposition analysis during curcumin adsorption in M-MOF-74 frameworks. Energy evolution profiles for (a) Co-MOF-74, (b) Mg-MOF-74, (c) Mn-MOF-74, (d) Ni-MOF-74, and (e) Zn-MOF-74 systems. Each panel displays four energy components: total energy (black line), Van der Waals contributions (red line), electrostatic interactions (blue line), and intramolecular energy changes (green line). The energy stabilization occurs primarily within the first 400,000 simulation steps, after which the systems reach equilibrium. Key findings: (1) Van der Waals interactions (red lines) dominate the adsorption energetics across all M-MOF-74 variants, contributing the largest stabilization. (2) Electrostatic contributions (blue lines) show metal-dependent variations, with Ni and Co exhibiting stronger electrostatic stabilization. (3) Intramolecular energy changes (green lines) remain relatively constant, indicating minimal conformational changes in curcumin upon adsorption. (4) Total energy profiles (black lines) confirm thermodynamically favorable.

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Systems exhibiting superior adsorption performance generally display lower total energies, higher van der Waals and electrostatic contributions, and lower intramolecular energies. This indicates stronger host-guest interactions, enhanced adsorption stability, and spontaneous adsorption processes. Conversely, materials with weaker adsorption performance show higher total energies and lower interaction energies, particularly reduced van der Waals and electrostatic forces, implying unstable adsorption prone to desorption.

The interaction energy data (Table 2) reveal a clear binding affinity trend: Mg-MOF > Mn-MOF > Co-MOF > Ni-MOF > Zn-MOF. This trend is consistent with the adsorption capacities discussed in Sect. 3.3, providing validation for our computational approach. The strongest interaction energy observed for Mg-MOF (−8040 ± 18.23 kcal/mol) can be attributed to the high charge density and strong Lewis acidity of Mg2+ centers, which facilitate robust electrostatic and coordination interactions with electron-donating functional groups in curcumin. The van der Waals contribution in Mg-MOF (−6390 ± 81.93 kcal/mol) is notably higher than other variants, suggesting favorable framework–drug contact geometry. In contrast, Zn-MOF exhibits the weakest binding energy (−4530 ± 19.10 kcal/mol), consistent with its lower drug loading performance. The moderate binding energies of Co-, Mn-, and Ni-MOF variants represent a balance between coordination strength and steric accessibility within the channels.

Table 2 Thermodynamic energy in the saturated State.
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These computational findings demonstrate that the metal center selection serve as a critical design parameter for tuning drug-MOF interactions, where the binding energy hierarchy directly translats to practical differences in drug loading and release behavior.

Differential analysis of adsorption mechanisms

The DFT + U method was applied to calculate and analyze the electronic interactions and coordination modes between curcumin and MOF-74 with different metal nodes (Fig. 6; Table 3).

Table 3 Single-molecule adsorption energy.
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Fig. 6
figure 6

Differential Analysis of Adsorption Mechanisms. The first column represents the differential charge density of curcumin and MOF materials, the second column represents the charge distribution projection of curcumin and MOF materials, and the third column represents the partial density of states of curcumin and MOF materials.

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For Mg-MOF-74, a notable coordination phenomenon occurs primarily at Mg1-O1 and Mg2-O2 sites. At these coordination points, the charge distribution in the Z direction is mainly concentrated at Mg1-O1 and Mg2-O2. Among them, the coordination at Mg1-O1 is stronger, while that at Mg2-O2 is relatively weaker. In the first coordination process, the p-orbital of Mg hybridizes with the p-orbital of O, while in the second coordination, the s-orbital of Mg hybridizes with the p-orbital of O. The s-orbital of Mg is usually associated with weaker, isotropic, and multi-center interactions, whereas the p-orbital exhibits stronger and directional dual-center interactions. It is worth noting that the anti-bonding orbitals formed during the magnesium-oxygen bond formation have higher energy, and when these anti-bonding orbitals reach a sufficiently high energy level, they may approach or even cross the Fermi level, thereby affecting the electronic structure of the material.

For the Zn node MOF-74, coordination also occurs at Zn1-O1 and Zn2-O2, and the charge distribution in the Z direction is concentrated at these two positions. In both the first and second coordination processes, the hybridization between the s-orbital of Zn and the p-orbital of O is the main mechanism, with the hybridization at position 2 being weaker. Due to its closed-shell structure and weak electrostatic field, Zn exhibits the weakest adsorption effect among the five metal nodes. This phenomenon indicates that Zn nodes in MOF-74 have limited adsorption capabilities.

In the case of Ni node MOF-74, coordination mainly occurs at Ni1-O1 and Ni2-O2, with charge distribution concentrated at these two positions in the Z direction. During the coordination process at both points, the d-orbital of Ni hybridizes with the p-orbital of O. Based on the degree of overlap of orbitals near the Fermi level, the hybridization at position 1 is stronger than that at position 2. At position 1, the strong hybridization between O1 and Ni1 results in the p-orbital of O1 having higher energy near the Fermi level, while the d-orbital of Ni1 experiences a decrease in energy. On the other hand, the hybridization between O2 and Ni2 is weaker, which does not significantly affect the d-orbital energy of Ni2. This suggests that Ni nodes in MOF-74 are more effective in adsorbing curcumin, and the coordination mode is more covalent.

When curcumin adsorbs onto Mn node MOF-74, the high-spin state of Mn results in its d-orbital having a d5 configuration. The half-filled d-orbital is relatively stable, thus reducing its ability to form feedback π-bonds, especially compared to Co and Ni nodes, but stronger than Zn. Coordination mainly occurs at Mn-O1 and Mn2-O2, where Mn’s d-orbital hybridizes with the p-orbital of O. The hybridization at position 1 is stronger than that at position 2, where the strong hybridization between O1 and Mn1 leads to a noticeable energy distribution of the p-orbital of O1 near the Fermi level, while the hybridization between O2 and Mn2 is weaker, leading to a wider band gap.

For Co node MOF-74, the Co d7 orbital configuration is not as stable as Mn’s d5 nor as saturated as Ni’s d8, but rather has a relatively flexible d-electronic structure, making its adsorption effect relatively good. Coordination mainly occurs at Co1-O1 and Co2-O2, where the hybridization between the d-orbital of Co and the p-orbital of O takes place. The hybridization between O1 and Co1 is stronger, which causes the p-orbital of O1 to have a significant energy distribution near the Fermi level, indicating that the coordination at position 1 is stronger, while that at position 2 is slightly weaker.

Overall, the hybridization between the metal d-orbitals and oxygen p-orbitals plays a crucial role in curcumin adsorption in MOF-74 The differences in electronic structures among different metal nodes directly modulate coordination strength and covalency, with Mg, Mn, Ni, and Co exhibiting superior adsorption performance compared to Zn.

Jahn-Teller distortion analysis

The distinctive adsorption characteristics of Mn2+ node can be elucidated by the Jahn-Teller effect. As a high-spin d5 ion, Mn2+ possesses a half-filled t₂g³ eg² configuration, which is particularly susceptible to geometric distortion, typically elongation or compression of the metal-ligand bonds, lowers the system’s overall energy by removing the degeneracy of the electronic states. In Mn-MOF-74, this manifests as asymmetric coordination between curcumin and Mn centers, with stronger Mn1-O1 and weaker Mn2-O2 interactions. The differential orbital hybridization and bond strength, driven by this distortion, fine-tune the coordination geometry and adsorption energetics. Consequently, Mn2+ exhibits an intermediate adsorption character, stronger than the purely electrostatic Mg2+ but less covalent than Ni2+ and Co2+, which explain its balanced and highly efficient adsorption performance.

Conclusion

This study presents a comprehensive multi-scale computational investigation into the interactions between curcumin and M-MOF-74 frameworks, elucidating the pivotal role of the metal node in governing adsorption behavior and performance. DFT analysis of curcumin accurately identified its reactive sites, with the HOMO primarily localized on the phenolic group, enabling metal coordination, and the LUMO distributed along the heptadienone chain, facilitating potential π-back bonding or stacking interactions. These electronic insights provide a theoretical foundation for understanding the molecular binding modes of curcumin within MOF structures. A clear structure-performance correlation was established. The metal node governs the pore diameter, the strength of curcumin-MOF interactions, and, consequently, the adsorption kinetics and capacity. Among the studied frameworks, Mn-MOF-74 and Co-MOF-74 exhibited the highest adsorption capacity and fastest kinetics, respectively, whereas Zn-MOF-74, characterized by weaker binding affinity, promoted the most efficient molecular diffusion.

Monte Carlo simulations quantified the thermodynamic driving forces, revealing a consistent trend in binding energies (Mg > Mn > Co > Ni > Zn). This hierarchy, governed by the interplay between electrostatic and van der Waals interactions, correlates well with experimentally reported drug loading capacities, thereby validating the reliability of the computational models.

DFT + U calculations provided atomistic insight into the adsorption mechanisms. The differences in adsorption efficiency were attributed to variations in orbital hybridization between the metal d-orbitals (or s/p orbitals for Mg/Zn) and the oxygen p-orbitals of curcumin. The distinct d-electron configurations of each metal, such as the stable high-spin d5 of Mn2+, the flexible d7 of Co2+, and the covalent d8 of Ni2+, governed the coordination strength and bonding nature. Consequently, Mg and transition metals such as Mn, Co, and Ni exhibited stronger coordination with curcumin compared to Zn.

Overall, this work demonstrates that the rational selection of the metal node in MOF-74 enables precise tuning of framework properties for optimized curcumin encapsulation and transport. The integrated electronic, kinetic, and thermodynamic insights presented herein provide a valuable theoretical framework for the design of advanced MOF-based drug delivery systems. The superior performance of Mn-MOF-74 and Co-MOF-74 highlights their potential as promising candidates for experimental validation and future application in controlled-release delivery system.