Phototriggered adhesive hydrogels integrating Mg/Quercetin MOFs for synchronous regulation of inflammation and angiogenesis in diabetic wounds

Yunshu Yang; Bin Tang; Menghan Zhou; Jiayi Sun; Can Qiu; Huaman Geng; Yajie Wang; Yanan Zheng; Yujie Hua; Guanyu Wang; Guangdong Zhou; Yingying Huo; Di Wang

doi:10.1016/j.mtbio.2026.103547

. 2026 Aug 13;40:103547. doi: 10.1016/j.mtbio.2026.103547

Phototriggered adhesive hydrogels integrating Mg/Quercetin MOFs for synchronous regulation of inflammation and angiogenesis in diabetic wounds

Yunshu Yang ^a,^b,¹, Bin Tang ^c,¹, Menghan Zhou ^a, Jiayi Sun ^a, Can Qiu ^a, Huaman Geng ^a, Yajie Wang ^a, Yanan Zheng ^a, Yujie Hua ^d,^e, Guanyu Wang ^b, Guangdong Zhou ^d,^e,^⁎, Yingying Huo ^d,^e,^⁎⁎, Di Wang ^a,^⁎⁎⁎

PMCID: PMC13499488 PMID: 42633382

Abstract

Chronic wounds affect over 20% of diabetic patients, imposing substantial socioeconomic and personal burdens. The diabetic wound microenvironment is characterized by hyperglycaemia, oxidative stress, persistent inflammation, and vascular damage, which disrupt tissue homeostasis and significantly hinder healing. The development of innovative multifunctional hydrogels is essential for treating diabetic wounds within such complex microenvironments. Based on metal-organic framework nanomaterials, this study introduces a dual-network crosslinked adhesive GelNB/HAMA hydrogel incorporating magnesium ions and Quercetin-based metal-organic frameworks (denoted as MgQu@GelNB/HAMA). In vitro experiments revealed that Mg-quercetin metal-organic framework (MgQu) promotes macrophage polarization from M1 to M2 type, scavenges reactive oxygen species, and stimulates neovascularization. Photopolymerization technology is employed to solidify the hydrogel into a dressing, ensuring strong adhesion to the wound site and minimizing secondary tissue damage while facilitating sustained, controlled release of Quercetin and magnesium ions. In a dorsal wound model of diabetic mice, this in situ formed multifunctional hydrogel dressing effectively reduces excessive inflammation, enhances neovascularization, accelerates collagen tissue regeneration, and advances wound healing. By improving the pathological microenvironment of diabetes, this study presents a promising new strategy for diabetic wound repair.

Keywords: Diabetic wound healing, Hydrogels, Quercetin, Metal-organic frameworks, Wound dressing

Graphical abstract

Highlights

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MgQu coordinates Mg²⁺ and quercetin as both structural and therapeutic components.
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MgQu@GelNB/HAMA modulates ROS, M1-M2 polarization, angiogenesis and collagen repair.
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MgQu@GelNB/HAMA shows suitable viscoelasticity, rapid crosslinking and swelling.
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MgQu@GelNB/HAMA accelerates diabetic wound healing and advances tissue repair.

1. Introduction

Diabetes is a complex metabolic disorder affecting over 340 million people worldwide, with around 20% of these individuals developing diabetic wounds [1]. The intricate pathological microenvironment of diabetic wounds is characterized by hyperglycaemia, oxidative stress, excessive inflammation, and vascular deterioration, all of which disrupt local homeostasis [[1], [2], [3], [4], [5]]. This presents a significant challenge to the wound healing process, severely hindering recovery and compromising patient health. Conventional clinical dressings, such as gauze, bandages, and foam sponges, provide symptomatic relief through compression but fail to systematically improve the local pathological environment or restore functional integrity to the affected area [6]. Recently, hydrogels have shown considerable promise in wound care due to their breathability, water absorption, and tissue-mimetic mechanical properties, which foster a moist environment conducive to tissue regeneration [[7], [8], [9], [10], [11], [12]]. However, the dynamic stages of chronic wound healing—such as inflammation, proliferation, and remodeling—require hydrogels to perform distinct functions at various time points. Thus, there is a critical need for adhesive, multifunctional hydrogel dressings capable of sustained release throughout the entire healing process [13].

Currently, the mechanical strength and properties of single-component hydrogels fall short of meeting the demands of wound dressings, highlighting the need for more effective strategies that promote healing and regulate the wound microenvironment [[14], [15], [16]]. Hyaluronic acid methacrylate (HAMA) is a biocompatible and biodegradable material, with a surface rich in CD44 ligands that enhance cell adhesion and proliferation [17,18]. The HAMA chain, containing abundant modifiable hydroxyl and carboxyl groups, provides suitable mechanical strength and is widely used in injectable hydrogels [18,19]. It can mimic the natural extracellular matrix (ECM), guide cell proliferation and differentiation [20,21], and deliver essential growth factors during tissue regeneration [15], making it highly applicable in tissue engineering. GelNB, a photosensitive polymeric material derived from gelatin modified with o-nitrobenzyl alcohol (NB), incorporates cell-adhesive RGD sequences and enzymatically degradable sites, facilitating cellular adhesion, proliferation, and differentiation. Its exceptional biocompatibility and biodegradability make it a promising option for wound dressings. The drug delivery system, combining GelNB and HAMA, forms a high-strength, highly adhesive hydrogel obtained through photoinitiated polymerization and crosslinking using a photoinitiator (NAP). Compared to single-component hydrogels like GelMA, this dual-network photocrosslinked hydrogel offers enhanced structural stability and superior mechanical properties [18,19], making it suitable for tissue engineering applications [22], including the construction of three-dimensional scaffold structures. To optimize wound repair, it is essential to improve the wound microenvironment and address the specific needs of each healing phase [23]. Conventional hydrogels, with their limited drug delivery and microenvironmental regulation capabilities, are inadequate for diabetic wound management. Therefore, the development of multifunctional hydrogel wound dressings tailored to the distinct requirements of each healing phase is crucial [24].

Quercetin, a flavonoid found abundantly in apples, onions, and tea (primarily as β-glycosides) [25], is a yellow, bitter compound that is water-insoluble but soluble in alcohol and lipids. Its structural diversity, wide availability, potent pharmacological effects, and low risk of adverse reactions have garnered significant scientific interest.

As is well known, the antidiabetic drug metformin exerts its effects by activating AMPK. Quercetin activates adenosine monophosphate kinase (AMPK) in skeletal muscle, which in turn stimulates Akt and GLUT4 receptors on the cell membrane, promoting the uptake of glucose into cells via GLUT4 receptors for metabolism. This regulates blood glucose levels and achieves a hypoglycemic effect [26]. The hydroxyl and oxygen groups of quercetin bind to metal ions, producing biochemical and pharmacological properties that scavenge free radicals, thereby inhibiting excessive oxidation and the inflammatory environment [27]. Catalase (CAT) effectively counteract the damage caused by reactive oxygen species as a common antioxidant, while quercetin enhances CAT expression levels by inhibiting reactive oxygen species and alleviating oxidative stress. In addition, quercetin can inhibit the expression levels of nitric oxide synthase (iNOS) and cyclooxygenase COX-2 protein in macrophages induced by lipopolysaccharide(LPS) in a concentration dependent manner [28].

Quercetin's superior anti-inflammatory, antioxidant, and antiviral properties enable the modulation of various disease-related intracellular and extracellular signalling pathways, making it effective in treating conditions such as diabetes, Alzheimer's disease, arthritis, and cardiovascular disorders [29,30]. During the inflammatory phase of wound healing, Quercetin can activate the Wnt/β-catenin signaling pathway [31,32], thereby restoring normal biological processes such as epidermal stem cell proliferation, keratinocyte differentiation and migration, and hair follicle regeneration. The structure of Quercetin incorporates phenol, carbon-carbon double bonds, and hydroxyl groups, which contribute to its antioxidant capacity. The inherent hydroxyl group scavenges free radicals, reducing oxidative stress and cellular damage caused by excess reactive oxygen species (ROS) [33].

By inducing HO-1 (heme oxygenase-1), Quercetin inhibits inflammatory mediators such as IL-1β, IL-6 and TNF - α [34]. While HO-1 tends to promote M2 phenotype, so quercetin treatment increased CD206-positive M2 macrophages and reduced iNOS-positive M1 macrophages, thus. Simultaneously, it enhances the levels of pro-inflammatory cytokines and suppresses excessive inflammatory responses. Thus it also facilitates the conversion of M1 macrophages to M2 macrophages, improving macrophage polarization in diabetic wounds [33]. This enhances the release of repair-related factors by M2 macrophages, accelerating wound healing [35]. Consequently, Quercetin demonstrates anti-inflammatory and wound-healing properties via M2 macrophages, offering promising potential for wound treatment. Quercetin promotes the proliferation and migration of L929 cells [32], enhances the synthesis and deposition of extracellular matrix (ECM) to provide a structural foundation for neotissue formation. Quercetin can activate the vascular endothelial growth factor signaling pathway and upregulate the expression of Angiogenin-1 [36] and VEGF [32,37], enhance vascular endothelial cell proliferation and angiogenesis to provide adequate oxygen and nutrient supply for tissue repair, enhanced fibroblast distribution and collagen deposition in wound tissues.

Despite its limited clinical use in wound healing due to low bioavailability, poor solubility, and restricted transdermal absorption, Quercetin's low molecular weight and modifiable chemical structure present opportunities for drug development. Nano assembly delivery can be used to improve drug solubility, stability, and local retention issues [38,39]. Previous studies have synthesized various Quercetin derivatives with low toxicity and high biological activity through structural optimization, improving both solubility and bioavailability compared to the parent compound. Quercetin's 3-hydroxy, 5-hydroxy, and 4-carbonyl groups enable complex formation with metal ions, supporting the development of suitable drug delivery systems.

Magnesium, an essential trace element in the human body, is involved in over 300 enzymatic reactions and regulates glucose metabolism [40,41]. Magnesium deficiency has been linked to a higher risk of several chronic diseases, particularly type 2 diabetes, through its effects on insulin resistance and glucose metabolism [42]. Magnesium ions also play a pivotal role in wound healing due to their angiogenic properties. Magnesium ions promote angiogenesis through several mechanisms, including the activation of pro-angiogenic factors like vascular endothelial growth factor (VEGF). Under hyperglycemic conditions, Mg²⁺ has been reported to promote endothelial migration and tube formation through activation of the PI3K/AKT/mTOR signaling axis. Recent evidence indicates that Mg²⁺ regulates endothelial tip-cell specification through VEGFA–VEGFR2/Notch1 signaling crosstalk and induces YAP nuclear translocation, thereby promoting endothelial migration, filopodia formation, stalk-cell proliferation and vascular network maturation. However, the rapid release and local accumulation of magnesium ions at wound sites can lead to cytotoxicity [43], limiting the effectiveness of conventional therapies. The coordination between Mg²⁺ and natural polyphenols can integrate complementary antioxidant and regenerative functions [44]. Consequently, drug delivery systems that enable controlled release of Quercetin and magnesium ions are necessary to fully harness their immunomodulatory, pro-angiogenic, and diabetes-risk-reducing effects. Previous studies have shown that Quercetin may exert synergistic effects with Mg²⁺released from MgO during osteogenesis, while simultaneously promoting endothelial progenitor cell (EPC)–mediated angiogenesis and exhibiting antioxidant activity [45]. Numerous studies have shown that the complex of quercetin and metal has reduced toxicity of metals, enhanced the biological activity and higher antioxidant capacity compared to quercetin due to metal chelation [[46], [47], [48]]. A class of crystalline porous compounds was formed by the coordination of inorganic metal ions and organic ligands—this study synthesizes the MgQu MOF using magnesium ions and Quercetin. MOFs have recently emerged as a research focus in drug delivery due to their high drug-loading capacity, controllable release properties, tunability, and targeting capabilities [[49], [50], [51], [52], [53]]. The potential nanozyme-like catalytic activity of MgQu may provide additional advantages for diabetic wound treatment [54,55].

We developed a photo-crosslinked dual-network drug-loaded hydrogel dressing, MgQu@GelNB/HAMA, as a dressing for diabetic wounds (Fig. 1). Unlike previous studies where MOFs were used as drug-loaded nanomaterial. our MgQu framework is constructed through Mg²⁺ and quercetin coordination, where the metal ion and organic ligand both act as structural components and therapeutic regulators. The dual-network composite hydrogel demonstrated superior mechanical properties compared to single-component hydrogels. With a tensile modulus, the hydrogel ensured stable adhesion and maintained integrity on the wound surface during normal movements, thereby minimizing further tissue trauma. Microscopic rod-shaped MOFs (MgQu) were uniformly dispersed within the hydrogel. The MgQu@GelNB/HAMA hydrogel matrix facilitated the release of Quercetin, exerting antioxidant effects and promoting the polarization of macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Meanwhile, MgQu facilitated sustained Mg²⁺ release, enhancing endothelial cell migration and promoting neovascularization. In diabetic mouse dorsal wound models, the multifunctional MgQu@GelNB/HAMA hydrogel dressing effectively reduced excessive inflammation, stimulated neovascularization, and promoted collagen tissue regeneration at the wound site. In summary, the photocrosslinked dual-network hydrogel dressing loaded with the MOF MgQu exhibited mechanical properties that supported sustained drug release. This novel drug-loaded hydrogel dressing continuously acted on the wound while modulating the wound microenvironment, offering a promising solution for treating chronic diabetic wounds.

2. Results and discussion

2.1. Preparation and biological evaluation of MgQu

The primary challenge in the treatment of diabetic wounds is reversing the pathological microenvironment, which can be effectively addressed through an ideal drug delivery system. Quercetin has been shown to reduce inflammation and oxidative stress, while magnesium ions promote new blood vessel formation. To harness their respective functions for diabetes-related wound healing, the MOF MgQu (Green powders) was synthesized using a hydrothermal (solvothermal) method at 40 °C in an aqueous reaction solution containing Quercetin (Yellow powders), magnesium chloride (White) (Fig. S1), and sodium hydroxide (Fig. 2a). Solvothermal/hydrothermal method is a common synthesis method for MOFs [56,57]. At the microscopic scale, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed that MgQu has a rod-like structure with an average length of 1.38 μm and an average width of 0.31 μm. The length and width distributions of MgQu followed a Gaussian distribution (Fig. 2d and e). Transmission X-ray diffraction (XRD) analysis confirmed that MgQu consists of carbon (C), oxygen (O), and magnesium (Mg), with an elemental composition of 59.6% carbon, 38.5% oxygen, and 1.9% magnesium (Fig. 2c), confirming the successful synthesis.

MgQu exhibited prominent diffraction peaks mainly within 10–30°, with the strongest reflections at approximately 12° and 27°. Although several peaks overlapped with the characteristic regions of native quercetin, their altered intensities, widths, and overall pattern indicate that Mg²⁺ coordination disrupted the original quercetin crystal packing and formed a reorganized Mg–quercetin coordination phase. Meanwhile, the characteristic MgCl₂·6H₂O reflections at approximately 21–22° and 33–35° were absent or markedly weakened, suggesting disruption of the precursor lattice. Thus, the MgQu pattern was distinct from a simple superposition of the two precursors. Additionally, X-ray photoelectron spectroscopy (XPS) was used to characterize the composition of MgQu (Fig. S2). Comparing the XPS spectra of the C1s orbital for MgQu and Quercetin, and the Mg1s orbital for MgQu and MgCl₂, the presence of a C1s orbital at 288-282 nm and a Mg1s orbital near 1304 nm was confirmed, verifying the incorporation of Mg²⁺ and Quercetin into the prepared MgQu (Fig. 2f).

Fourier transform infrared spectroscopy (FTIR) shown in Fig. 2g was used to characterize the molecular structures of MgQu. The broad O–H stretching band of quercetin shifted from 3405 to 3331 cm⁻¹ after Mg²⁺ incorporation, indicating alteration of the hydrogen-bonding environment and possible involvement of phenolic hydroxyl groups in Mg²⁺ coordination. The vibration peaks observed at 1521.2 cm⁻¹, 1489.82 cm⁻¹, and 1448.15 cm⁻¹ of MgQu are basically consistent with the infrared spectrum of Quercetin representing the aromatic ring C=C, indicating that MgQu retains the aromatic ring skeleton of Quercetin. The vibration peaks observed at 1320.55 cm⁻¹, 1250.92 cm⁻¹, 1201.24 cm⁻¹, 1167.52 cm⁻¹, and 1090.15 cm⁻¹ in MgQu are consistent with the infrared spectra of phenolic hydroxyl and ether bonds in Quercetin structure, indicating that MgQu exhibits stretching vibrations of phenolic C-O, flavonoid heterocyclic C-O-C, and O-H in Quercetin. MgQu retained a low wavenumber vibration peak (618.67 cm⁻¹) related to Mg at 620.26 cm⁻¹, but the intensity and shape of this peak changed compared to MgCl₂·6H₂O, indicating that the hydration and lattice environment around Mg²⁺ changed after coordination assembly, causing it to transition from a low-energy π - π transition state to another state [58]. Fig. 2h, i, j consists of three sets of N₂ adsorption desorption isotherms and corresponding pore size distribution curves. MgQu exhibits a broader and markedly higher pore size distribution than the two raw materials, with pore volume primarily concentrated in the tens-of-nanometers range and tailing to 100–200 nm, indicating enhanced meso/macroporosity and a possible multi-level stacking structure among nanorods. The increase in total pore volume and interparticle accessible space may provide channels for subsequent diffusion and release of Mg²⁺ and quercetin. The markedly increased nitrogen uptake of MgQu indicates that Mg²⁺–quercetin coordination induced substantial reconstruction of the accessible surface and pore architecture.

To further investigate the potential of MgQu as a regenerative agent for diabetic wound treatment, the release profiles of Quercetin and Mg²⁺ ions from MgQu were measured. Full-spectrum detection revealed a prominent characteristic peak at 370 nm(Fig. S3) with an intensity of 4.50414 for MgQu. Good cellular compatibility and hemocompatibility are essential requirements for pharmaceuticals. CCK-8 assays and hemolysis tests revealed that MgQu exhibits favorable biocompatibility. To evaluate its cellular compatibility, MgQu solutions in DMEM were prepared at concentrations ranging from 0.05 to 50 μg/mL and co-cultured with mouse fibroblast cells (L929) for 48 h. It was observed that at MgQu concentrations below 50 μg/mL, L929 cell viability remained unaffected compared to the control group cultured in blank medium. Culturing solutions containing various concentrations of MgQu showed minimal impact on fibroblast proliferation, with relative cell survival rates exceeding 70% (Fig. 2k). These results indicated that MgQu concentrations below 50 μg/mL did not exhibit apparent toxicity to L929 cells, demonstrating favorable biocompatibility. In hemocompatibility analysis, the hemolysis rate of MgQu was evaluated using a red blood cell hemolysis assay. With ddH₂O as the positive control (showing a 100% hemolysis rate) and PBS as the negative control (showing a 0% hemolysis rate), quantitative results indicated that the hemolysis rate of fresh rabbit blood in MgQu/PBS solutions ranging from 0.05 to 50 μg/mL remained below 5%. The hemolysis rate of MgQu was negligible, fully meeting biomaterial safety standards (<5%) [59], and demonstrating excellent hemocompatibility (Fig. 2l). Further investigation using the CAM/PI staining kit confirmed that the live/dead cell ratio in the experimental group of L929 cells co-cultured with MgQu medium did not show a statistically significant decrease compared to the control group at 24, 48, and 72 h. The majority of cells exhibited good viability (green) and a spindle shape, while a minority were dead (red) (Fig. S4). After 24 h, the mortality rates for the control and experimental group cells were approximately 0.01%. By 72 h, the mortality rate in the control group was around 0.1%, while the experimental group reached approximately 0.14% (Fig. S5). The results from the Live/Dead staining assay indicated that at the operational concentration, MgQu did not induce significant cellular toxicity in L929 cells, further confirming its good cellular compatibility.

The release profiles of Mg²⁺ and quercetin from MgQu and MgQu@GelNB/HAMA were evaluated over time. MgQu exhibited a relatively rapid and continuous release of Mg²⁺, reaching a cumulative concentration of approximately 44–45 μg/mL by day 15. In contrast, MgQu@GelNB/HAMA showed a slower and more gradual release profile, with a cumulative Mg²⁺ concentration of approximately 25–26 μg/mL at the same time point(Fig. 2m). Quercetin also displayed sustained release from both systems. The cumulative quercetin concentration gradually increased after the initial 24 h and reached approximately 2.3 mg/mL for MgQu and 2.0–2.1 mg/mL for MgQu@GelNB/HAMA by day 21(Fig. 2n). The 0-24 h burst release phase(Fig. S6) showed slow release, and there is no risk of accumulating a large amount in early release. The hydrogel-loaded system exhibited a restricted Mg²⁺ diffusion and a slower quercetin release profile. This behavior may be attributed to the combined effects of MgQu coordination dissociation and diffusion through the crosslinked hydrogel network. Overall, MgQu@GelNB/HAMA provided sustained dual release of Mg²⁺ and quercetin, with reduced early release and prolonged delivery compared with MgQu alone. This dual-barrier release behavior may help maintain effective local concentrations of both bioactive components throughout the inflammatory, proliferative, and remodeling phases of wound healing. The release amount data was analyzed to calculate the release kinetics of each group. For the MgQu group, the Mg²⁺ release profile showed the best fit to the first-order model, and the release kinetics formula is as follows: C_t = 45.779 (1-e^−0.24398t), R² = 0.9954, suggesting a concentration-dependent release behavior characterized by rapid initial release followed by a gradual plateau. For the MgQu@GelNB/HAMA group, the release profile was best described by the Korsmeyer–Peppas model. The release kinetics formula for magnesium ions in the MgQu@GelNB/HAMA group is C_t = 5.671t^0.543, R² = 0.9958. The release exponent n = 0.543 indicates an anomalous transport mechanism, suggesting that Mg²⁺ release from MgQu@GelNB/HAMA was governed by the combined effects of molecular diffusion, hydrogel swelling/relaxation, and gradual dissociation of the MgQu coordination framework. The Qu release profile of MgQu was best fitted by the first-order model, the release constant k for the MgQu-group MOF is 0.1656, with the equation F_t = 100 (1-e^−0.1656t), R² = 0.9888, indicating a concentration-dependent release behavior with rapid initial release followed by a gradual plateau. In contrast, MgQu@GelNB/HAMA showed the best fit to the Korsmeyer–Peppas model, with the equation F_t = 11.273t^0.804, R² = 0.9554. The release exponent n = 0.804 indicates an anomalous transport mechanism governed by diffusion, hydrogel swelling/relaxation, and gradual dissociation of the MgQu coordination framework. While the release of Mg in physiological environment is jointly controlled by surface reactions and Mg²⁺ diffusion [60].

2.2. Preparation and mechanical evaluation of MgQu@GelNB/HAMA

The development of adhesive, multifunctional hydrogel wound dressings with sustained-release capabilities throughout the entire wound healing process is critical. Such dressings must suppress inflammation, promote cell proliferation, and support tissue remodeling, addressing a key need in the field. In this study, a MgQu@GelNB/HAMA hydrogel, loaded with MgQu MOFs, was developed for treating diabetic wounds, which are characterized by a microenvironment that hinders tissue repair, elevated inflammation, and ROS levels. For hydrogel preparation, the photosensitive polymer GelNB, derived from o-nitrobenzyl alcohol-modified gelatin, and the methacrylated biopolymer HAMA were synthesized. These components were mixed in specific ratios with LAP as the photoinitiator to form a pre-crosslinked gel solution. MgQu nanorods were then incorporated and evenly dispersed. Upon exposure to ultraviolet light at 365 nm, the photoinitiator initiated polymerization and crosslinking reactions, resulting in the formation of a high-strength dual-network drug-loaded hydrogel (Fig. 3a). This dual-network hydrogel exhibited superior mechanical strength compared to single-component hydrogels. The polymerization of GelNB and HAMA formed microscopic HA particles, reinforcing the matrix structure of the hydrogel. Under UV irradiation, GelNB undergoes photoactivation, generating aldehyde groups and converting the hydroxyl group on the benzene ring into an aldehyde group. This microscopic structural change induces macroscopic photopolymerization of the hydrogel (Fig. 3b). The physicochemical properties of the blank hydrogel GelNB/HAMA and the drug-loaded MgQu@GelNB/HAMA were characterized. At the macroscopic level, the unpolymerized hydrogel existed as a fluid liquid, while the photopolymerized hydrogel transformed into a solid gel morphology (upper panel of Fig. 3c). Cryo-electron microscopy was used to observe the morphological features of the hydrogels (Fig. 3c). Both hydrogels exhibited a dense porous structure with similar pore sizes, but MgQu@GelNB/HAMA displayed a more compact network structure. The incorporation of MgQu into the microporous structure of the hydrogel filled the spaces within the matrix, creating more complex inter-pore connections and resulting in a denser gel (Fig. 3c).

Fig. 3 — Characterization of MgQu@GelNB/HAMA hydrogel dressings. (a) Preparation process of MgQu@GelNB/HAMA. (b) Principle of photopolymerization of hydrogels. (c) Macroscopic and cryo-EM microstructures of GelNB/HAMA and MgQu@GelNB/HAMA before and after photopolymerization. (d-f) (n = 1)Rheological behavior of GelNB/HAMA and MgQu@GelNB/HAMA hydrogels: frequency sweep (d), amplitude sweep (e), and photo-crosslinking (f) tests. (g) Degradation rate(%) of GelNB/HAMA and MgQu@GelNB/HAMA in 0-5 h. (h) Degradation rate(%) of two groups of hydrogels in 5 h. (i) Swelling ratio(%) of hydrogel in 0-24 h. (j) Swelling ratio(%) of two groups of hydrogels in 24 h. (k) Macro-characterization of hydrogel adhesion on pig skin, including initial state, inversion, bending, and encapsulation states. Tensile stress-strain curves of hydrogels in three adhesion tests: (l) t-test, (m) Lap shear, (n) Tensile shear. (o) Tensile stress-strain relationship from hydrogel tensile testing. (p) Relationship between tensile stress and strain in cyclic tensile testing of the hydrogel. (q) Comparison of Young's modulus, (r)maximum force, (s)maximum strain, and (t)displacement at maximum force during tensile testing of GlNB/HAMA and MgQu@GelNB/HAMA.

The flexibility and extensibility of hydrogel dressings are critical for maintaining their structural stability and integrity. Given that diabetic wounds may occur on body parts with significant ranges of motion, it is essential to ensure that the wound dressing exhibits suitable viscoelastic properties. Fig. 3d–f presents rheological testing of the hydrogels, comparing the mechanical properties of blank and drug-loaded dual-network hydrogels. Analysis of the variations in storage modulus (G′) and loss modulus (G″) between the two hydrogel groups revealed that the incorporation of MgQu nanorods slightly reduced the storage elastic modulus of GelNB/HAMA, with no significant decrease in the loss modulus (Fig. 3d). At a frequency of 1 Hz, both hydrogels were subjected to shear strain (Strain%). As strain increased from 0.01% to 100%, G′ and G″ of MgQu@GelNB/HAMA remained relatively stable (Fig. 3e). At this point, the hydrogel material showed no structural damage, maintaining internal stability and demonstrating elastic recovery. In contrast, for the GelNB/HAMA hydrogel, G′ and G″ remained stable until the strain amplitude reached 20%, exhibiting strain-dependent viscoelastic behavior. The G′ sharply declined at approximately 20% strain, and as strain increased, the storage modulus of GelNB/HAMA decreased to approximately 5% of its initial value (Fig. 3e). This indicated that the microstructure of GelNB/HAMA underwent irreversible yielding, fracture, or restructuring. Conversely, the loss modulus markedly increased at around 60% strain, where G′ and G″ intersected (denoting the yield stress), indicating that the hydrogel exhibited localized viscous behavior. The blank hydrogel exhibited a fracture strain of approximately 20%, whereas the MgQu-incorporated sample exceeded 100%. Within the tested strain range, both G′ and G″ of MgQu@GelNB/HAMA remained within the linear viscoelastic regime without exceeding the critical strain. These results demonstrated that the incorporation of MgQu enhanced the hydrogel's tensile properties. At a frequency of 1 Hz, it exhibited enhanced resistance to higher strain amplitudes, underwent elastic reversible deformation over a broader strain range, and demonstrated reduced energy dissipation and improved mechanical stability, thereby minimizing the probability of viscous deformation energy loss. Fig. 3f shows that both hydrogel groups exhibited a convergence point for G′ and G″ around 30 s, indicating photopolymerization occurs at approximately this time, marking a transition in the hydrogel's material properties. Hydrogel swelling, degradation, mechanical stability, and drug release are closely governed by the architecture and crosslinking density of the polymer network [61]. The swelling and degradation state of hydrogel photographed at different time points were shown in Fig. S7.The two hydrogels exhibited a time-dependent degradation profile, with rapid mass loss during the first 3 h and degradation levels approaching approximately 90% after 5 h (Fig. 3g). Although MgQu@GelNB/HAMA showed a slightly lower degradation rate than GelNB/HAMA during the early stage, no significant difference was observed between the two groups at 5 h(Fig. 3h). These findings indicate that the incorporation of MgQu did not markedly alter the overall short-term degradation behavior of the GelNB/HAMA network. Fig. 3g exhibited that MgQu incorporation significantly increased the swelling ratio at 24 h from approximately 115% to 127% (Fig. 3j). both hydrogels absorbed water rapidly and gradually reached swelling equilibrium at approximately 12 h (Fig. 3i). The 24 h swelling ratio of MgQu@GelNB/HAMA was significantly higher than that of GelNB/HAMA (**p < 0.01). This increase may be attributed to the hydrophilic hydroxyl and oxygen-containing groups of MgQu and possible changes in the internal network structure of the hydrogel. Therefore, MgQu incorporation enhanced the water-absorption capacity of the hydrogel without significantly affecting its short-term degradability, suggesting improved potential for wound-exudate absorption while maintaining biodegradability.

The rapid closure of tissue injuries significantly reduces the risk of infection [62]. Thus, the adhesion capability of the hydrogel was assessed. As shown in Fig. 3k, the photopolymerized hydrogel was applied to porcine skin and subjected to inversion, twisting, wrapping, and immersion tests. The hydrogel remained firmly adhered to the skin surface without detachment, demonstrating its adhesion properties for wound dressing applications at the macroscopic scale. Additionally, the hydrogel's 180° peel (T-peel) adhesion strength, tensile adhesion strength, and shear adhesion strength were evaluated (Fig. 3l–n), yielding displacement-force relationship curves. In both T-peel and lap shear tests, the applied force stabilized once displacement reached a certain threshold (Fig. 3l and m). During tensile testing, stress peaked rapidly before displacement reached 1 mm, then decreased with further displacement (Fig. 3n). No significant differences in interfacial toughness, tensile strength, or shear strength were observed between the two hydrogel groups, indicating comparable cohesive properties. The hydrogel dressing exhibited immediate and favorable adhesion, enhancing biocompatibility and promoting tissue regeneration under physiological conditions [59]. However, improper adhesion during dressing replacement or removal often leads to secondary tissue damage. To evaluate the extensibility of the hydrogels, tensile and cyclic tensile tests were conducted, comparing the tensile stress–strain curves of the two hydrogel groups (Fig. 3o and p). In Fig. 3k, tensile stress increased with tensile strain, with both hydrogel groups exhibiting a fracture strain of 120–140% and a fracture stress near 700 kPa. Endless fatigue performance was assessed via continuous tensile testing. As shown in Fig. 3m, hysteresis loops, indicative of energy dissipation, were observed during each strain cycle. Despite minimal time intervals between cycles, the loading curves remained highly similar due to energy dissipation within the polymer chains. During tensile testing, parameters including Young's modulus, maximum force prior to failure, maximum strain, and displacement corresponding to maximum force were compared between the two hydrogel groups, revealing no significant intergroup differences (Fig. 3q–t). These results demonstrated that the two hydrogel networks had comparable entanglement and crosslinking densities within their molecular chains. The deformability of the hydrogel dressings enables complete coverage of irregularly shaped skin wounds, while preventing microbial invasion. By expanding to effectively seal and protect the wound site upon tissue contact, the hydrogel reduces the risk of further injury or contamination.

2.3. MgQu promotes cell migration and angiogenesis

The cell migration assay was conducted to evaluate the ability of MgQu to promote tissue formation and wound healing, while the angiogenesis assay was employed to assess the angiogenic capability of MgQu. The working concentration validation of MgQu drug is within the non-toxic concentration range of HUVEC(Fig. S8(a)). HUVEC cells were co-incubated with different media for 24 h, and the migration distances of HUVEC cells in each group were compared to the blank control (Fig. 4a). In MgQu, Mg²⁺ and quercetin directly participate in the coordination structure and function simultaneously as structural constituents and bioactive components. In our study, the sustained release curve has confirmed the dual delivery of Mg2+ and quercetin. We have separately set up quercetin combined with magnesium ion groups for comparison with MgQu, both of which are effective in vitro. If free Mg and quercetin are added at the same time, it is impossible to determine which particle is exerting its effect. Observations revealed that cell migration in the Mg²⁺ group significantly increased compared to the blank control, reaching approximately 1.6 times the distance of the blank control group. No significant enhancement in cell migration was observed in the Quercetin group compared to the blank control. However, the migration distance in the MgQu group was significantly higher than that of the blank control, reaching approximately 1.3 times that of the blank group (Fig. 4b). Existing literature suggests that Mg²⁺ promotes angiogenesis, which aligns with the current experimental findings [43]. Due to the slow release of Mg²⁺, the migration distance in the MgQu group was lower than in the Mg²⁺ group. This cell migration assay demonstrated that MgQu promotes neovascularization, primarily through the functional role of Mg²⁺ in wound healing. Concurrently, Quercetin may indirectly contribute to the angiogenic microenvironment by mitigating oxidative stress [30]. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis of VEGF gene expression revealed significantly elevated VEGF levels in the Mg²⁺, Quercetin, and MgQu groups compared to the blank control (Fig. 4c).

The in vitro angiogenic activity of the hydrogel was further evaluated using the angiogenesis assay with HUVEC cells. As shown in Fig. 4d, the MgQu group exhibited the largest number of nodes and has the longest average length of pipe. The number(Fig. 4e) and length(Fig. 4f) of tubes in Mg²⁺ group and Quercetin group were higher than those in the control group and lower than those in MgQu group, indicating that Mg²⁺ and Quercetin significantly promotes angiogenesis in vitro. Magnesium ions have the effect of promoting angiogenesis [45], while Quercetin may promote angiogenesis by improving the oxidative stress microenvironment [63]. These results demonstrate that MgQu exhibits favorable biocompatibility and multiple bioactivities, including promoting cell proliferation and migration, promoting angiogenesis, which meet essential requirements for diabetic wound healing.

2.4. MgQu promotes fibroblast proliferation and collagen production

During wound healing, fibroblasts promote ECM remodeling by facilitating its deposition. Fibroblasts facilitate wound contraction and accelerate the healing process through differentiation into contractile myofibroblasts. Quercetin promotes the proliferation and migration of L929 cells [32], enhances the synthesis and deposition of extracellular matrix (ECM) to provide a structural foundation for neotissue formation. The working concentration validation of MgQu drug is within the non-toxic concentration range of L929(Fig. S8(b)). EdU staining(Fig. 4g) showed that MgQu markedly enhanced fibroblast proliferation, as evidenced by the highest proportion of EdU-positive cells among all groups. Although Mg²⁺ and free quercetin produced modest increases in EdU incorporation, neither group differed significantly from the control, whereas the MgQu group exhibited a significant increase(Fig. 4h). Furthermore, free quercetin and MgQu significantly increased hydroxyproline content, whereas Mg²⁺ alone showed no evident effect(Fig. 4i). Consistently, the mRNA expression levels of COL1(Fig. 4j), COL3(Fig 4k), and α-SMA(Fig. 4l) were markedly upregulated by quercetin and were further elevated in the MgQu group. In contrast, Mg²⁺ alone did not significantly alter these extracellular matrix-related genes. Type III collagen plays an important role in early wound repair and granulation tissue formation, and COL1 is an important component of mature collagen fibers and wound extracellular matrix. Quercetin and MgQu can promote the expression of type I collagen genes in fibroblasts, enhance the transcription of type III collagen, and contribute to the early and late formation of matrix and granulation tissue in wounds. α-SMA is an important biomarker of myofibroblasts. Quercetin and MgQu can both promote the expression of α - SMA(Fig. 4l), with MgQu having the most significant effect, suggesting that it may promote the transformation of fibroblasts into myofibroblast like phenotypes with contractile function, thereby accelerating wound contraction. Collectively, these findings indicate that MgQu promotes fibroblast proliferation, collagen synthesis, extracellular matrix formation, and myofibroblast-associated activation, thereby potentially contributing to granulation tissue formation and wound contraction.

Data are presented as mean ± standard deviation from three independent experiments (n = 3). Statistical significance was analyzed using one-way ANOVA followed by Tukey's multiple-comparisons test. ns, P > 0.05; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

2.5. MgQu suppressed inflammation and scavenged ROS in vitro

To evaluate the anti-inflammatory efficacy of MgQu, a lipopolysaccharide (LPS)-induced oxidative damage model in RAW264.7 cells was established, and the effects were assessed via immunofluorescence staining. LPS-stimulated RAW264.7 macrophages were co-incubated with Mg²⁺, Quercetin, and MgQu for 24 h. To rigorously assess the anti-inflammatory effects, cells were co-incubated with phalloidin and DAPI. Macrophages exhibiting M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes were identified using CD86 and CD206 markers. Fluorescence intensity was observed under confocal microscopy to assess the impact of different treatments on macrophage polarization. Compared to the control group, the LPS group exhibited significantly higher green fluorescence intensity, indicating that the inflammatory environment promoted macrophage differentiation towards the pro-inflammatory M1 phenotype. The LPS + Mg²⁺ and LPS+Qu groups showed varying degrees of fluorescence attenuation compared to the LPS group (Fig. 5a), with reductions of approximately 40% and 30%, respectively (Fig. 5b). As a wound dressing, the sustained-release behavior of MgQu and its gel matrix ensures long-lasting effects following a single application, enabling continuous regulation and reversal of the pathological microenvironment throughout the wound healing process [64]. The LPS + MgQu group exhibited a further reduction relative to the LPS + Mg²⁺ and LPS + Qu groups, with a decrease of approximately 60% compared to the LPS group (Fig. 5b), although the final fluorescence intensity remained higher than that of the control group. As shown in Fig. 5c, no significant change in the green fluorescence intensity representing CD206 was observed between the LPS and control groups. However, compared to the untreated LPS group, the LPS + Mg²⁺ and LPS+Qu groups exhibited fluorescence enhancements, with intensities approximately 2 and 3 times higher than those of the LPS group (Fig. 5d). The LPS + MgQu group exhibited the most significant enhancement, with fluorescence intensity reaching approximately 3.5 times that of the LPS group (Fig. 5d). This indicates increased CD206 expression in the Mg²⁺, Quercetin, and MgQu groups. These findings suggest that MgQu inhibits macrophage polarization towards the M1 phenotype while enhancing M2 macrophage activation, thereby attenuating inflammatory responses. Immunohistochemical experiments further confirmed the anti-inflammatory effects of Mg²⁺, Quercetin, and MgQu. LPS stimulation successfully induced an inflammatory response, while all treatment groups showed reduced CD86 fluorescence intensity, indicating that MgQu effectively suppressed the expression of inflammatory cytokines. Simultaneously, increased CD206 fluorescence intensity in all treatment groups demonstrated MgQu's promotion of anti-inflammatory factor expression. This mechanism suppresses excessive inflammatory responses during wound healing, regulates the wound microenvironment, and facilitates tissue repair.

Oxidative stress is another hallmark of infected wounds, with ROS levels reflecting cellular oxidative damage resulting from both physiological functions and environmental factors [59,65]. In hypoxic wounds of diabetic patients, ROS levels increase dramatically, often exceeding the body's natural clearance capacity [59]. Maintaining stable intracellular ROS levels and preventing an imbalance in oxidative-antioxidative processes is crucial. To assess MgQu's antioxidant capacity, an LPS-induced oxidative damage model was established in RAW264.7 cells. ROS scavenging rates for the control, Mg²⁺, Quercetin, MgQu, and positve control groups were measured using DCFH-DA probe staining (Fig. 5e). DCFH-DA staining showed that the control group exhibited only weak green fluorescence, whereas LPS stimulation markedly increased intracellular fluorescence, confirming the successful establishment of the in vitro oxidative stress model (Fig. 5e). Compared with the LPS group, treatment with Mg²⁺, quercetin, or MgQu significantly reduced the fluorescence intensity (Fig. 5f). Compared to the LPS group, the relative fluorescence intensities of the LPS + Mg²⁺, LPS + Quercetin, and LPS + MgQu groups exhibited approximately reductions of approximately 95.55%, 98.93%, and 99.20%. MgQu demonstrated superior antioxidant effects compared to Mg²⁺ and Quercetin, indicating that MgQu regulation significantly alleviated the oxidative stress in the pathological microenvironment. These findings suggest that MgQu effectively scavenges ROS at the wound site, benefiting diabetic wound treatment. Its antioxidant activity is partly due to the properties of Quercetin and potentially to the catalytic activity of the MgQu nanorods. Fig. 5g and h shows elevated mRNA expression levels of M1 macrophage-associated inflammatory factors (IL-1β and TNF-α) in the LPS group compared to the control group via qRT-PCR, simulating the persistent and hyperactive inflammatory state characteristic of early wound healing. In contrast, with the inclusion of Mg²⁺, Quercetin, and MgQu, all three agents reduced IL-1β and TNF-α levels, with MgQu showing the most pronounced effect. Catalase (CAT) serves as an antioxidant cytokine, and LPS had no significant effect on its expression (Fig. 5j). Simultaneously, all three agents increased CAT and M2 macrophage marker IL-4 expression (Fig. 5i and j). Research has shown that Quercetin modulates pro-inflammatory cytokines (TNF-α) and interleukin-6 (IL-6), inhibiting oxidative stress that contributes to inflammation, arthritis, and diabetes [63].

The cell-free free-radical-scavenging activity of Mg²⁺, quercetin, and MgQu was evaluated using the DPPH assay. As shown in Fig. 5k, the control group displayed negligible DPPH scavenging activity, whereas the Mg²⁺, quercetin, and MgQu groups exhibited scavenging rates of approximately 27%, 67%, and 74%, respectively. All three treatment groups showed significantly higher DPPH radical-scavenging activity than the control group (p < 0.0001). Among the tested samples, MgQu exhibited the highest mean scavenging rate, followed by free quercetin and Mg²⁺. These results indicate that quercetin possesses strong direct free-radical-scavenging capacity and that its antioxidant activity was largely retained after coordination with Mg²⁺ to form MgQu. This study demonstrated the mechanism of MgQu which effectively reduced pro-inflammatory factor levels and enhanced anti-inflammatory factor expression by releasing Quercetin and Mg²⁺. This promoted macrophage polarization from the M1 to the M2 phenotype, enhanced CAT antioxidant gene transcription, and reduced ROS levels, thereby significantly alleviating the inflammatory response at the wound site (Fig. 5l). The mechanism, same as previous studies, showed reducing intracellular ROS can suppress pro-inflammatory macrophage activation, promote a CD206-positive M2-like phenotype, downregulate IL-6 and TNF-α, and increase IL-10 and VEGF expression [66]. Quercetin enhances the expression of endogenous antioxidants and participates in the regulation of macrophage polarization by activating the PI3K/Akt/NF-κB pathway [67]. Quercetin can activate the Wnt/β - catenin signaling pathway [31,32], thereby restoring normal biological processes such as epidermal stem cell proliferation, keratinocyte differentiation and migration, and hair follicle regeneration. Quercetin can inhibit the expression of M1 marker mRNA, such as CD86, TNF-α, IL-1β, and IL-6, while promoting the expression of M2 marker mRNA, such as CD206、Arg-1、IL-10 and TGF-β [67].

2.6. In vitro antibacterial test

The antibacterial activities of Mg²⁺, quercetin, and MgQu against Staphylococcus aureus(S.aureus) and Escherichia coli(E.coli) were evaluated using a colony-forming assay. As shown in Fig. 5m, abundant bacterial colonies were observed in the control groups for both strains. Treatment with Mg²⁺ markedly reduced the number of colonies, whereas free quercetin produced no evident reduction compared with the control. In contrast, MgQu treatment resulted in the fewest colonies for both S. aureus and E. coli. Quantitative analysis showed that the survival rates of S. aureus were approximately 100%, 30%, 105%–110%, and 5% in the control, Mg²⁺, quercetin, and MgQu groups, respectively (Fig. 5n). Mg²⁺ and MgQu significantly reduced bacterial survival compared with the control group (p < 0.0001), whereas quercetin did not exhibit an apparent antibacterial effect under the tested conditions. Similarly, the survival rates of E. coli were approximately 100%, 25%, 98%, and 18%, respectively (Fig. 5o). Both Mg²⁺ and MgQu significantly inhibited E. coli survival, while no significant difference was observed between the quercetin and control groups. Overall, MgQu exhibited the lowest mean survival rate for both bacterial strains, indicating strong antibacterial activity against both Gram-positive and Gram-negative bacteria.

Bacterial infection is a major obstacle to chronic wound healing, as persistent bacterial colonization can aggravate inflammation and delay tissue regeneration. In the present study, MgQu markedly reduced the colony-forming ability of both S. aureus and E. coli, suggesting broad-spectrum antibacterial potential. The inhibitory effect was more pronounced against S. aureus, whose survival rate decreased to approximately 5%, compared with approximately 18% for E. coli. This difference may partly result from the outer membrane of Gram-negative bacteria, which can act as an additional permeability barrier against antimicrobial agents.

2.7. MgQu@GelNB/HAMA promotes diabetic wound healing in vivo

Open wounds pose a significant risk of infection [68]. Drug-loaded hydrogels offer suitable mechanical properties, including adhesiveness and tissue-like flexibility, while the sustained-release drug MgQu exhibits favorable biological activities, such as anti-inflammatory, antioxidant, and vasculogenesis-promoting effects. Building on in vitro experiments, a skin wound model (Φ: 8 mm) was established using BKS-db/db black male mice (SPF grade, 42 days old). Full-thickness circular wounds with an 8 mm diameter were created on the backs of diabetic mice to evaluate the therapeutic efficacy of the drug-loaded hydrogel on chronic wounds. The mice were randomly assigned to the following groups: untreated control (naturally healing wounds), MgQu powder application, GelNB/HAMA hydrogel coverage, and MgQu@GelNB/HAMA hydrogel coverage. The wound modeling, treatment, and sampling procedures are illustrated in Fig. 6a. As shown in Fig. 6d, mouse blood glucose levels were maintained above 16 mM, confirming the successful establishment of the diabetic model. Throughout the 14-day in vivo experiment, all groups exhibited stable blood glucose levels, indicating normal biochemical parameters. Macroscopic observations of infected wounds were conducted on days 0, 3, 5, 7, 10, 12, and 14, with wound images and healing progress documented (Fig. 6b). Quantitative analysis revealed changes in relative wound area over the corresponding time points (Fig. 6c). Imaging revealed faster healing rates across all treatment groups compared to the untreated control group. The control group exhibited a wound closure rate of approximately 37.6% at day 14, while wounds in the MgQu@GelNB/HAMA group were completely closed by day 14. Quantitative analysis of relative wound area showed healing rates of approximately 57% for the MgQu group and 68% for the GelNB/HAMA group at day 14. By day 12, the MgQu@GelNB/HAMA group exhibited the most effective tissue healing, with a relative wound area of approximately 43%, significantly outperforming both the MgQu group (61%) and the control group (63%) (Fig. 6c).

The MgQu nanorods-loaded dual-network hydrogel dressing developed in this study aims to accelerate diabetic wound healing (angiogenesis and cell proliferation) by improving the adverse microenvironment through anti-inflammatory and antioxidant activities. To investigate the healing process, we performed haematoxylin and eosin (H&E) staining and Masson's trichrome staining. Wound healing quality was assessed via H&E staining on postoperative day 14. Compared to other groups, the MgQu@GelNB/HAMA group exhibited the smallest wound size and complete epidermal/dermal regeneration, with more orderly and thicker granulation tissue (Fig. 6e). Epidermal healing and neocortex formation were also observed in the MgQu and GelNB/HAMA groups. The neocortex in the GelNB/HAMA and MgQu@GelNB/HAMA groups exhibited greater smoothness, attributed to the hydrogel's maintenance of a moist wound healing environment. MgQu@GelNB/HAMA combined the anti-inflammatory and antioxidant properties of MgQu with the conformability of hydrogels as wound dressings, simultaneously accelerating healing and reducing scarring. These results demonstrate the superior therapeutic efficacy of MgQu@GelNB/HAMA for diabetic wounds.

Regarding tissue regeneration in diabetic wounds, MgQu, GelNB/HAMA, and MgQu@GelNB/HAMA significantly promoted collagen deposition (Fig. 6f). Collagen fibres are key indicators of ECM regeneration at wound sites [59]. As shown in Fig. 6f, Masson's trichrome staining revealed that the control group exhibited lighter blue areas representing collagen fibres with smaller coverage, indicating a higher proportion of newly formed, immature type III collagen, reduced total collagen deposition, sparse distribution, and early-stage granulation tissue. In contrast, the MgQu, GelNB/HAMA, and MgQu@GelNB/HAMA groups exhibited deeper blue staining with denser and more regular fibre arrangement. This indicated increased collagen deposition in the skin tissue, a higher proportion of mature type I collagen replacing the earlier type III collagen, and enhanced tissue mechanical strength due to the more orderly collagen arrangement, resulting in more mature granulation tissue. The more orderly collagen arrangement significantly enhanced tissue mechanical strength and promoted more mature granulation tissue. Additionally, richer follicular structures were observed in the dermis of the MgQu and MgQu@GelNB/HAMA groups (yellow arrows in Fig. 6f), indicating that the drugs possess potent regenerative-promoting capabilities, achieving functional healing. This phenomenon may be explained by MgQu's effective scavenging of ROS, which facilitates the transition of the wound from the inflammatory and proliferative phases into tissue remodeling and scar maturation stages. This process accelerated the transformation of proliferative granulation tissue into mature collagen deposition [69]. In Fig. 6f, quantitative analysis of hair follicle like structures shows that the hair follicle density in the MgQu and MgQu@GelNB/HAMA group was significantly higher than that in the control group and GelNB/HAMA group(Fig. S9). Hair follicle stem cells in newly formed hair follicles can migrate to the surface of the wound, differentiate into keratinocytes, and participate in the formation of new epidermis. The rich capillary network around hair follicles promotes angiogenesis and granulation tissue formation. The increased number of regenerated hair follicles indicates that MgQu@GelNB/HAMA promoted not only wound closure and collagen remodeling, but also the restoration of skin appendages, suggesting a higher quality of functional skin regeneration.

2.8. MgQu@GelNB/HAMA regulates the M1/M2 phenotype balance of macrophages in vivo

Diabetic wounds are commonly associated with local ischemia and tissue necrosis, caused by a hyperglycemic microenvironment that induces vascular dysfunction and persistent inflammation [70,71]. To evaluate the efficacy of MgQu@GelNB/HAMA in promoting diabetic wound healing, skin tissue samples from wound sites were analyzed through immunofluorescence and immunohistochemistry, focusing on inflammation, cell proliferation, collagen formation, and angiogenesis. Wound and adjacent skin tissue samples were collected on days 3 and 7 post-surgery for immunofluorescence analysis of CD86 and CD206, with fluorescent sections of wound tissue observed at 500 μm, 200 μm, and 50 μm scales. Inflammation peaked at 48 h, and by 72 h (day 3 sampling), the extent of normal inflammatory resolution could be assessed. In the control group, abundant bright red signals (CD86) were observed, overlapping with green CD68 signals to form yellow spots, indicating substantial infiltration of M1-type macrophages at the wound site and reflecting a robust pro-inflammatory state. In contrast, the MgQu, GelNB/HAMA, and MgQu@GelNB/HAMA groups showed markedly diminished red signal intensity (CD86), with a significant reduction in yellow spots (Fig. 7a), indicating a substantial decrease in pro-inflammatory M1 macrophage proportions following drug application and hydrogel treatment in the experimental groups. Fig. 7b shows DAPI/CD86/CD68 fluorescent staining sections harvested on day 7, when the wound entered the proliferative phase. The red signal (CD86) in the control group on day 7 was weaker and more sparse compared to day 3, suggesting reduced inflammation and entry into the initial stage of spontaneous healing. The MgQu and MgQu@GelNB/HAMA groups exhibited weaker red fluorescence intensity, reflecting lower inflammation levels. The GelNB/HAMA group showed no significant reduction in red fluorescence compared to the control group (Fig. 7e). Fig. 7e displays the M1 ratio (CD86/CD68) in sections from all four groups at days 3 and 7. At day 3, the M1 ratio was significantly lower in the MgQu, GelNB/HAMA, and MgQu@GelNB/HAMA groups compared to the control group, indicating that MgQu and the hydrogel promoted inflammation resolution and suppressed excessive inflammatory responses. Fig. 7c and d depict DAPI/CD206/CD68 fluorescently stained sections from days 3 and 7, respectively. The faint red signal in the control group indicated the persistence of the inflammatory phase, with most macrophages retaining the M1 phenotype without transitioning to M2. On day 3, the red signal (CD206) was stronger in the MgQu, GelNB/HAMA, and MgQu@GelNB/HAMA groups compared to the control group. Fig. 7f presents the M2 ratio (CD206/CD68) in the four groups at days 3 and 7. By day 7, the red signal (CD206) in the MgQu, GelNB/HAMA, and MgQu@GelNB/HAMA groups had become brighter and more extensively distributed (Fig. 7d), with significantly enhanced red fluorescence intensity (Fig. 7f). This indicated that the drug and hydrogel promoted macrophage polarization towards the M2 phenotype, initiating the wound repair program. The red fluorescence in the GelNB/HAMA group remained weaker and did not significantly exceed that of the control group by day 7, suggesting relatively fewer anti-inflammatory, reparative M2 macrophages. These results demonstrated that the drug successfully reversed the local wound immune microenvironment from a pro-inflammatory state to an anti-inflammatory repair state, facilitating the transition from the inflammatory to proliferative phase and accelerating the healing process. In summary, the MgQu@GelNB/HAMA photocrosslinked dressing effectively mitigates inflammation, scavenges excess ROS in diabetic wounds, and promotes cellular proliferation and angiogenesis, thereby accelerating diabetic wound healing. By day 14, the expression of CD68 was extremely low in all groups, indicating that the number of macrophages in the late stage of wound healing was very small, and the expression of CD86 and CD206 was also low(Fig. S10). There was no significant difference between the groups. This indicates that as wound healing progresses, macrophages no longer continue to accumulate at the wound site, and the inflammatory response typically subsides. These findings suggest that the principal effect of MgQu@GelNB/HAMA was not to maintain continuous suppression of inflammation throughout the entire healing period, but rather to accelerate inflammation resolution during the early stage. Specifically, the earlier reduction in CD86 expression and increase in CD206 expression in the treatment groups indicate that MgQu@GelNB/HAMA promoted an earlier transition from a pro-inflammatory microenvironment toward a reparative state. This timely immune transition likely provided favorable conditions for subsequent angiogenesis, collagen deposition, and re-epithelialization, thereby contributing to accelerated wound closure.”

Fig. 7 — Histological Immunofluorescence and Immunohistochemical Analysis. (a) DAPI (blue)/CD86 (red)/CD68 (green) images on Day 3. (b) DAPI (blue)/CD86 (red)/CD68 (green) images on Day 7. (c) DAPI (blue)/CD206 (red)/CD68 (green) images on Day 3. (d) DAPI (blue)/CD206 (red)/CD68 (green) images on Day 7. Observed at different magnifications (scale bar: 500 μm, scale bar: 200 μm, scale bar: 50 μm). Quantitative analysis was performed on the relative fluorescence intensities of CD86 (e) and CD206 (f). (g) CD31 immunohistochemical sections from day 15 mice. (h) The number of CD31-positive vessels per visual field. (i) Relative microvessel density in CD31 sections. (j) Collagen I immunohistochemical sections from day 15 mice. (k) Relative area of collagen in collagen I immunohistochemical sections. Error bars denote mean ± standard deviation (n = 3). ns: no significant difference, p > 0.05; *p < 0.05; **p < 0.01; ***p < 0.001. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

2.9. MgQu@GelNB/HAMA promotes angiogenesis, collagen fiber repair, and tissue regeneration in vivo

During the proliferative phase, epithelial regeneration is essential for restoring skin barrier function, reducing water loss, and lowering the risk of infection. Inadequate nutrient supply due to limited local angiogenesis is a key factor contributing to delayed wound healing [72]. To assess neovascularization, wound and adjacent skin tissues were harvested 14 days post-surgery and analyzed using CD31 immunohistochemistry. CD31, a transmembrane protein expressed specifically on newly formed vascular endothelial cells, serves as a reliable marker for vascularization in injured tissues. CD31 staining revealed inadequate tissue remodeling in the control group (Fig. 7g), while the MgQu@GelNB/HAMA group showed dense granulation tissue formation, near-complete regeneration of the epidermal structure, and clear formation of hair follicle and sebaceous gland structures. Fig. 7h shows the counting of positive blood vessels in CD31 immunohistochemistry images. The wound samples for each group were obtained from at least 3 different mice. In order to maintain consistency, the scaling ratio of each image is within the range of 10.3-11.6, and it is ensured that there is no significant difference in the skin layer direction of each image. In the wound area, select a region of interest selection with the same area to manually count CD31 positive vascular staining signals. Fig. 7k is the relative area of collagen in collagen I immunohistochemical sections. The wound samples for each group were obtained from at least 3 different mice. In order to maintain consistency, the scaling ratio of each image is within the range of 4.5-4.9, and it is ensured that there is no significant difference in the skin layer direction of each image. In the wound area, select region of interest selection with the same area, and the COL1 staining related signals in these images are recognized by ImageJ. The number of vessels per field of view in the CD31 immunohistochemical analysis was highest in the MgQu@GelNB/HAMA group (Fig. 7h), correlating with the significant elevation of VEGF expression levels, indicating potent tissue regenerative capacity. This enhanced angiogenesis may be attributed to the sustained release of Mg²⁺ from MgQu@GelNB/HAMA. Furthermore, the restoration of the oxidative stress microenvironment is critical for neovascularization in diabetic wounds. Quercetin release reduces excessive ROS, contributing to the promotion of angiogenesis in diabetic wounds. At day 14 post-surgery, tissue samples were collected and evaluated for collagen synthesis and accumulation through immunohistochemical staining for type I collagen. Adequate collagen deposition forms the foundation for a robust ECM, where the oriented arrangement of collagen fibres and increased matrix deposition stimulate ECM formation. Fig. 7j illustrates collagen deposition across treatment groups at day 14 post-treatment, with brown areas indicating higher collagen deposition. Visually, the MgQu@GelNB/HAMA group exhibited larger brown areas, with deeper staining and more uniform distribution. Quantitative analysis revealed that drug and hydrogel treatments significantly promoted collagen deposition, with the MgQu@GelNB/HAMA group showing the highest collagen deposition during wound healing—five times higher than the control group, representing a statistically significant difference (Fig. 7k). This outcome confirms the successful transformation of granulation tissue into collagen-rich, low-cell-density skin tissue. In summary, these findings highlight the potential mechanisms by which drug-loaded hydrogels treat infected wounds: anti-inflammatory effects, inhibition of M1 macrophage polarization, promotion of M2 polarization, facilitation of the transition from the inflammatory to proliferative phase, enhancement of angiogenesis and collagen deposition, and a pivotal role in promoting epithelial regeneration and tissue remodeling, ultimately improving overall healing in diabetic wounds.

Assessing the repair and regeneration of collagen fibers involves evaluating their alignment. Fig. 8a shows Sirius Red immunohistochemical staining and polarized light staining of collagen fibers, revealing their macroscopic alignment and growth patterns. A lower proportion of fibers aligned between −20° and +20° indicates disordered collagen fiber arrangement. Horizontally aligned fibers facilitate cushioning and lubrication, while vertically aligned fibers provide support and load-bearing capacity [73]. Quantitative results regarding collagen fiber orientation are shown in Fig. 8b. In the MgQu@GelNB/HAMA group, 29.89% of collagen fibers were aligned between −20° and +20°, followed by the MgQu group (23.87%) and the GelNB/HAMA group (24.61%). The control group exhibited the lowest value (21.03%), indicating disordered collagen fiber alignment (Fig. 8b). To better illustrate these trends, the results were plotted in a polar diagram, confirming that the MgQu@GelNB/HAMA group demonstrated the most favorable collagen fiber alignment and overall repair outcomes (Fig. 8c).

3. Conclusions

In conclusion, a MgQu MOF-loaded photocrosslinked dual-network hydrogel has been developed. This hydrogel combines GelNB and HAMA, with the covalent crosslinked GelNB/HAMA network providing excellent adhesion properties. This ensures prompt physical closure of wounds while mitigating the risk of secondary injury associated with traditional wound dressing removal. The hydrogel also exhibits favorable skin compatibility, self-healing capacity, and mechanical resilience, allowing it to withstand high-frequency mechanical stresses in dynamic wound environments. The MgQu MOF incorporated within the hydrogel exerts anti-inflammatory, antioxidant, and pro-angiogenic effects. The drug-loaded hydrogel achieves synergistic regulation of the wound microenvironment through the sustained release of MgQu nanorods. This hydrogel modulates the diabetic wound microenvironment via multiple pathways, including ROS scavenging, promoting M1-to-M2 macrophage conversion, and enhancing angiogenesis, thereby accelerating healing in diabetic infected wounds. In vivo experiments demonstrate that the microenvironmental regulation function of the drug-loaded hydrogel significantly promotes angiogenesis, epidermal regeneration, and collagen deposition, ultimately leading to comprehensive improvement in wound healing. This multifunctional hydrogel exhibits epidermal adaptability and immunomodulatory effects, delivering remarkable therapeutic outcomes and offering a promising new therapeutic option for diabetic wounds.

4. Experimental section

4.1. Materials

Magnesium chloride hexahydrate (MgCl_2·6H2O) and Quercetin were procured from Sigma-Aldrich Company(America). 95% ethanol was purchased from Shanghai Xifa Chemical Reagent Co., Ltd. (China), DMEM (Dulbecco's modified eagle medium) was purchased from Hyclone Laboratories Inc., Utah (USA), DMSO (dimethyl sulfoxide) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. (China), macrophage RAW 264.7 was purchased from ATCC official website, phosphate buffer solution (PBS) was purchased from Beijing Soleibao Technology Co., Ltd. (China), Cell Counting Kit-8 (CCK-8) kit was purchased from Shanghai Biyuntian Biotechnology Co., Ltd. (China), C57BLKS/J black male mice (SPF grade, 42 days old) were purchased from Saiye (Gu'an) Biotechnology Co., Ltd. (Suzhou, China), Haematoxylin Eosin (Haematoxylin Eosin) The xylene eosin (HE) staining kit and Masson staining solution kit were purchased from Servicebio, the 4% paraformaldehyde fixative was purchased from Beijing Biyuntian Biotechnology Company (China), and DAPI, CD68, CD86, CD206 were purchased from Daixuan Biotechnology (China), GelNB hydrogel and HAMA were obtained from Lingjiu Medical. Dichlorofluorescein (DCFH-DA) was purchased from Beijing Solarbio Science & Technology Co., Ltd. Calcein/PI live/dead cell viability assay kit, cytotoxicity assay kit, and Calcein AM were purchased from Beyotime.

4.2. Synthesis of metal-organic frameworks

To prepare the solution, 4 g of sodium hydroxide was dissolved in 50 mL of deionized water with stirring to obtain a sodium hydroxide solution. Subsequently, 2 g of Quercetin and 2 g of magnesium chloride hexahydrate were added, resulting in a mixed alkaline solution containing organic compounds and metal ions using solvent (water)-thermal method. [33,74]. This mixture was transferred to a 50 mL brown glass screw-top reagent bottle. A rotor was placed at the bottom of the bottle, and the centrifuge tube was positioned in a water bath heating pot. The solution was magnetically stirred at room temperature for 1 h. Throughout the process, the dissolution of Quercetin was monitored using pH paper and a pH standard color chart to ensure the solution maintained a pH of 10. This facilitated the hydrothermal reaction between Quercetin and magnesium salt, forming the magnesium-Quercetin MOF (MgQu). After 1 h, the magnetic stirrer was turned off, and the reagent bottle was placed in the water bath at a constant temperature of 40 °C for 24 h. Upon completion, the water bath was turned off, and the reagent bottle was allowed to cool naturally to room temperature.

The suspension was transferred to a centrifuge tube and centrifuged in a high-speed refrigerated centrifuge (12,000 rpm, 4 °C, 10 min). The supernatant was discarded, and the precipitate was sequentially resuspended in 95% ethanol and deionized water, followed by sonication (20 kHz) for 10–15 min to ensure complete particle dispersion. This procedure was repeated three times to ensure the purity of the product, effectively removing impurities and unreacted sodium hydroxide from the suspension until the supernatant was free of visible impurities. Each sonication and centrifugation step was performed thoroughly to prevent residual impurities from compromising product purity. The washed precipitate was placed in a constant-temperature drying oven and dried at 40 °C for 24 h to remove moisture and ethanol, yielding magnesium-Quercetin MOF (MgQu) powder. The sample was then transferred to a vacuum freeze-dryer, frozen at −60 °C for 6 h, and placed in a vacuum environment for sublimation at room temperature. Upon completion of vacuum drying, the sample was immediately sealed to prevent moisture absorption and stored in a −4 °C refrigerator for subsequent use.

4.3. Fourier transform infrared (FTIR) spectroscope

The FTIR spectrum of the MgCl₂·6H₂O, Quercetin, and MgQu-MOFs were analyzed by Fourier transform infrared-attenuated total reflectance(DTGS KBr). Samples were lyophilized prior to test. Before acquiring the transmission infrared spectra of the samples, a background spectrum was collected. All the spectra were obtained between 4000 cm⁻¹ and 400 cm⁻¹.

4.4. Sustained-release experiment

MgQu (1 mg) was weighed and dissolved in 1 mL of phosphate-buffered saline (PBS (pH 7.4)). The absorbance of the drug solution was measured across the 230–1000 nm wavelength range using an enzyme-linked immunosorbent assay (ELISA) reader. Full-spectrum detection was performed to analyze ultraviolet absorption peaks at specific wavelengths, determining the drug's absorption wavelength at 370 nm. For the control group, 1 mL of pure water was used; for the drug group, 1 mg of MgQu was added to 1 mL of pure water and mixed thoroughly. For the drug-loaded hydrogel group, 1 mg of MgQu was incorporated into 500 μL of blank hydrogel GelNB/HAMA, which was cross-linked via UV irradiation to yield MgQu@GelNB/HAMA, then combined with 1 mL of PBS. The blank hydrogel group was prepared by cross-linking 500 μL of blank hydrogel GelNB/HAMA via UV irradiation, followed by the addition of 1 mL of PBS.

All experimental and control groups were placed in a 37 °C constant-temperature shaking incubator for 24 h. On days 1, 3, 5, 7, 10, 14, and 16(Fig. 2m)

On days 1, 3, 5, 7, 10, 14, 16, 21, and 24(Fig. 2n), samples from each group were centrifuged. The supernatant from each centrifugation was collected, and the optical density (OD value) at 370 nm was measured using an ELISA reader. Queretin release quantities at each time point were recorded according to the standard curve. On days 1, 3, 5, 7, 10, 14, and 16(Fig. 2m), the supernatants at different time points were collected and the concentration of Mg²⁺ was measured by ICP-OES. After each sampling, 1 mL of PBS was added to resuspend the precipitate from each group, and the samples were returned to the 37 °C shaker for continued agitation until the next sampling and testing. This experimental protocol allows the evaluation of the sustained-release properties of MgQu, analyzing its release rate and total release quantity at different time points. The experimental results provide valuable data for further optimization of the drug carrier's design and application. In addition, the sampling intervals (hour3, 6, 12, 18, 24) was chosen for early time points (hours 0-24), which would better characterize the burst release phase.

4.5. Release kinetics analysis

The cumulative release profiles of Mg²⁺ and quercetin from MgQu and MgQu@GelNB/HAMA were fitted using zero-order, first-order, and Korsmeyer–Peppas kinetic models. The zero-order model was expressed as:

Equation 1.

(1)

where Ct is the cumulative amount released at time t, C₀ is the initial released amount, and k₀ is the zero-order release constant.The first-order model was expressed as:

Equation 2.

(2)

where C_t and C_∞ represent the cumulative amounts released at time t and at release equilibrium, represent the cumulative amounts released at time t and at release equilibrium, respectively, and k is the first-order release constant. First-order release describes a concentration-dependent process in which the release rate gradually decreases as the releasable component is depleted. The Korsmeyer–Peppas model was expressed as:

Equation 3.

(3)

where k is a kinetic constant related to the structural and geometrical characteristics of the delivery system, and n is the release exponent reflecting the dominant transport mechanism. For cylindrical hydrogel samples, n ~ 0.45 indicates Fickian diffusion, 0.45<n < 0.89 indicates anomalous or non-Fickian transport involving both diffusion and polymer-chain relaxation, and n ~ 0.89 indicates case-II transport approaching zero-order release [75,76].

Nonlinear regression was performed for each dataset, and the most appropriate model was selected according to the coefficient of determination (R²) and the agreement between the fitted and experimental release profiles. An R² value greater than 0.95 was considered indicative of a satisfactory fit [77].

4.6. Swelling and enzymatic degradation assessment

For determining the swelling kinetics of GelNB/HAMA and MgQu@GelNB/HAMA, freeze-dried hydrogels were precisely weighed to obtain the initial dry mass (W₀) and then submerged in the buffer solutions. Then the swelling ratio of the composite hydrogels was measured by gravimetric method using PBS (pH 7.4)at room temperature. At the predetermined time point, sample were taken out from solutions, dried in oven and weighted. After incubation for 24 h, the samples were removed, gently blotted with filter paper to remove excess surface liquid, and immediately weighed (Wt). The swelling ratio was calculated using the following equation:

Equation 4.

(4)

The enzymatic degradation behavior of GelNB/HAMA and MgQu@GelNB/HAMA hydrogels was evaluated in PBS containing 0.01% (w/v) collagenase type I at 37 °C. Collagenase type I was selected because it can enzymatically cleave collagen-like peptide sequences derived from the gelatin component of GelNB, thereby providing an accelerated model for evaluating the susceptibility of the hydrogel network to protease-mediated degradation. Hydrogel samples with a known initial dry mass (W₀₎ were immersed in the degradation medium. At predetermined time points (3,6,12,18, and 24h), the samples were removed from the container, rinsed with distilled water to remove residual enzyme, and to obtain the residual mass (Wt). The degradation ratio was calculated as:

Equation 5.

(5)

4.7. Hemolysis assay

Experimental Details. Fresh rabbit blood was collected into an EDTA anticoagulant tube. The blood was centrifuged at 3000 rpm for 20 min, and the supernatant was discarded. PBS solution, twice the volume of the supernatant, was added, and the blood was centrifuged again at 3000 rpm for 20 min. The supernatant was discarded, and this washing process was repeated until the supernatant PBS became colorless, yielding a thoroughly washed erythrocyte pellet. MgQu/PBS mixtures were prepared at concentrations of 50, 20, 10, 5, 2, 1, 0.5, and 0.05 μg/mL for the test samples, following the same concentration gradient as the CCK-8 assay. Five microliters of blood cells were aspirated from the bottom of the anticoagulant tube into a 1.5 mL Eppendorf tube. For the eight experimental groups, 1 mL of the respective MgCl₂/PBS mixture was added. The negative control group received 1 mL of PBS, and the positive control group received 1 mL of ddH₂O. After thorough mixing of each group's solution with the erythrocyte pellet, the samples were incubated at 37 °C in a constant-temperature oven for 2 h. After incubation, the samples were centrifuged at 1500 rpm for 3 min, and color differences in the supernatant from each group were compared with those of the positive and negative control groups. The supernatant from each group was transferred to a 96-well plate, and the hemolysis rate was estimated by measuring absorbance at 540 nm.

Equation 6.

(6)

4.8. In vitro biocompatibility testing (CCK-8 and live/dead assay)

To determine the non-toxic concentration range of the prepared MgQu solution and identify the optimal concentration for cell proliferation, a series of MgQu concentration gradients were established based on previous studies. These studies demonstrated that Quercetin concentrations above 100 μg/mL inhibit macrophage proliferation, while concentrations below 39 μg/mL have no morphological effect on macrophages and suppress the release of the inflammatory mediator NO and the expression of iNOS. MgQu was dissolved in DMSO to prepare solutions at concentrations of 50, 20, 10, 5, 2, 1, 0.5, and 0.05 mg/mL. These solutions were then mixed 1:1000 wit h high-glucose DMEM cell culture medium, yielding a series of MgQu/DMSO mixtures at concentrations of 50, 20, 10, 5, 2, 1, 0.5, and 0.05 μg/mL MgQu/DMEM mixtures, along with a 1:1000 DMSO/DMEM diluent.

Fibroblasts were seeded into four 96-well plates, each designated for the 0 h, 24 h, 48 h, and 72 h groups. Each well contained 4000 cells, cultured overnight in standard high-glucose DMEM medium. After overnight incubation, cells were prepared for treatment. Under light-protected conditions, the 0 h group had its culture supernatant discarded, and CCK-8 was added. Simultaneously, the 24 h, 48 h, and 72 h groups had their culture medium discarded. Each plate contained one blank control group, one negative control group, and eight experimental groups at different concentrations, with five replicate wells per group. The blank control group received 200 μL of DMEM, the negative control group received 200 μL of a 1:1000 DMSO/DMEM mixture without MgQu, and the experimental groups received 200 μL of MgQu/DMEM mixtures at concentrations of 50, 20, 10, 5, 2, 1, 0.5, and 0.05 μg/mL. Following drug treatment, the three well plates were incubated for 24, 48, and 72 h, respectively. The medium was then removed, replaced with 20 μL of CCK-8 reagent, and incubated for an additional 3 h. OD values were measured at a wavelength of 450 nm.

Equation 7.

(7)

MgQu@GelNB/HAMA was suspended above cell culture dishes, allowing the culture medium to submerge the drug-loaded hydrogel and enabling its sustained-release components to co-incubate with L929 cells, constituting the experimental group. The control group consisted of standard high-glucose medium co-cultured with L929 cells to assess the hydrogel's cellular compatibility. Cell viability was measured at 24, 48, and 72 h by adding CAM/PI reagent. As shown in Fig. S4, at 24, 48, and 72 h, the live/dead cell ratio of L929 cells in the experimental group did not significantly differ from that in the control group. At 24 h, the apoptosis rates for both the control and experimental groups were approximately 0.01%. At 72 h, apoptosis in the control group was around 0.1%, while the experimental group reached approximately 0.14%. These results suggest that the MgQu concentration released from MgQu@GelNB/HAMA did not induce significant cytotoxicity. Live/dead staining revealed that the majority of cells survived with intact morphology, with only a small number of dead cells exhibiting red fluorescence (Fig. S4), confirming good cellular compatibility.

4.9. In vitro cell migration and angiogenesis

In the proliferative phase of wound healing, the rapid proliferation of new capillaries and endothelial cells is essential for promoting granulation tissue formation, thereby accelerating wound healing. To investigate the effects of Mg²⁺, Quercetin, and MgQu on cell proliferation and migration in a chronic wound environment, a scratch assay was performed on human umbilical vein endothelial cells (HUVECs). An artificial wound was created by scratching a line across the confluent HUVEC monolayer. Cytarabine at 10 mM was added to inhibit cell proliferation. Cells were grouped into the blank control, Mg²⁺, Quercetin, and MgQu groups. The blank control group was treated with standard high-glucose DMEM medium. The Quercetin group received DMEM supplemented with 10 μM Quercetin, the Mg²⁺ group received DMEM with 5 mM Mg²⁺, and the MgQu group received DMEM with 10 μg/mL MgQu. After drug administration to the experimental groups, cell migration and wound closure were observed. Images were captured 6 h post-scratch to compare gap closure rates between each group and the control. A higher gap closure rate indicated the drug's ability to promote wound closure in vitro. Additionally, the ability of MgQu to promote cell migration and tubule formation was evaluated by observing tubule formation, branching points, and average tube length. The MgQu group demonstrated improvements in both branching points and tube length compared to the control group, indicating that MgQu promotes angiogenesis and wound healing in vitro.

4.10. EdU incorporation assay

Cell proliferation was measured using Cell-Light KFluor488 EdU Kit (Ribobio, Guangzhou, China). Fibroblasts with a density of 1 × 10⁵ were seeded into 6-well plates and incubated at 37 °C for 24 h. They were then treated with different groups for 24 h. Then, 50 μM EdU was added to each well for 2 h. The cells were immobilized with 4% paraformaldehyde for 10 min and then infiltrated with 0.5% Triton X-100 for 15 min. The nuclei were stained with Hoechst 33,342 and were then observed under an inverted fluorescence microscope.

4.11. Estimation of total collagen by hydroxyproline assay

Hydroxyproline assay was performed to measure total collagen content in fibroblast culture supernatant (24 h treatment). Briefly, the fibroblast culture supernatants were digested with 6 nM hydrochloric acid overnight at 110 °C followed by vacuum drying of the samples. After resuspending the samples in citrate acetate buffer, a colored reaction was done by adding isopropyl alcohol, chloramine T, and Ehrlich's reagent. The samples were incubated at 25 °C for 18 h, and intensity of the red color was measured at 558 nm using Varioskan Multimode Reader (Thermo Fisher). With the help of a standard curve, hydroxyproline content in the unknown samples was calculated. The amount of collagen was calculated by multiplying hydroxyproline content by a factor of 8.2.

4.12. Detection of ROS generation/anti-inflammatory properties and antioxidant capacity

Macrophage suspension (2 mL) was seeded into each well of a six-well plate and incubated at a constant temperature for 24 h. Experimental groups included the control group, LPS group, LPS + Mg²⁺ group, LPS + Qu group, and LPS + MgQu group. The LPS concentration co-cultured with the cells was 100 ng/mL, the MgQu concentration was 10 μg/mL (within the non-toxic concentration range determined by the CCK-8 assay), the Mg²⁺ concentration was 5 mM (Mg²⁺ concentration chosen was sourced from this article [78]), and the Quercetin concentration was 10 μM. Upon reaching approximately 80% confluence, the high-glucose DMEM medium was removed, the cells were washed with PBS, and the drug + LPS mixture was added according to the five groups. After a 24-h incubation, the medium was discarded, and the cells were washed with PBS. Two milliliters of DCFH-DA probe diluted in serum-free DMEM was added to each well, resulting in a final DCFH-DA concentration of 10 μM. The six-well plate was placed in the incubator, shielded from light, for 30 min. After incubation, the probe was removed, and the cells were washed multiple times with PBS. One milliliter of PBS was added per well, and fluorescence images were acquired under a confocal microscope using green light excitation at 480 nm.

To further assess the anti-inflammatory efficacy of the drugs, in addition to quantifying ROS scavenging using the DCFH-DA probe, immunofluorescence staining was employed to examine the ability of polarized macrophages to adopt an anti-inflammatory phenotype. Cells were divided into the following groups: blank control, LPS, LPS + Mg²⁺, LPS + Qu, and LPS + MgQu, with concentrations of LPS, Mg²⁺, Quercetin, and MgQu consistent with the previously outlined groupings. Climbing sheets were placed at the bottom of 24-well plates to facilitate cell growth and attachment. After 24 h of drug treatment, the supernatant was removed, cells were washed with pre-chilled PBS, and fixed with 4% paraformaldehyde in the dark for 15–30 min. Following PBS washes, the cells were permeabilized with 0.2% Triton X-100 in PBS for 10 min and then washed with PBS. Bovine serum albumin (BSA) powder was dissolved in PBS to prepare a 2–3% BSA solution, and the cells were incubated with this solution for 1 h, after which it was discarded. Each cell group was divided into two subgroups and incubated overnight at 4 °C with primary antibodies CD86 and CD206, respectively. The following day, the cells were washed with PBS and incubated at room temperature with secondary antibodies 594 and 488 for 1 h each. After PBS washing, cells were stained with DAPI for 10 min in the dark. Coverslips were placed upside down on slides coated with an anti-fade agent, and fluorescence images were captured under a confocal microscope. Blue light excitation with green light emission was used to measure fluorescence intensities for CD86 and CD206, green light excitation with red light emission for cytoskeletal morphology, violet light excitation with blue light emission for nuclear morphology, and blue light excitation with green light emission for primary antibody CD86 or CD206 fluorescence.

For Fig. 5b–d, f, the immunofluorescence staining samples for each group were obtained from at least 3 different slides. When shooting with a fluorescence microscope, the gain settings such as laser power, excitation light intensity, and exposure time for each fluorescence channel should be kept consistent. Perform quantitative analysis of fluorescence intensity on fluorescently stained images using ImageJ. I separately detected the integrated density of blue fluorescence (DAPI), red fluorescence (palloidin), and green fluorescence (CD86 or CD206) images of cells within the same field of view after background subtraction. The fluorescence intensity calculated in this experiment is the relative fluorescence intensity per unit area. The calculation formula of fluorescence intensity per unit area of each picture is Fluorescence intensity =  $\frac{Green fluorescence indensity (CD 86 or CD 206)}{Blue fluorescence indensity (DAPI)}$ . The formula for relative fluorescence intensity(multiples) is Relative fluorescence intensity =  $\frac{Fluorescence intensity of one group}{Fluorescence intensity of control group}$ .

Antioxidant capacity of the MgQu was assessed by monitoring their ability to eliminate 2,2-diphenyl-1-picrylhydrazyl (DPPH•). For the DPPH• assay, the pure MgCl₂·6H₂O, Quercetin and MgQu was added to the DPPH• solution in methanol. The absorbance of the samples and blank was measured at 517 nm. Percentage of DPPH• scavenging = (Ab—As)/Ab × 100%, where Ab and As are the absorbance of the blank and sample at 517 nm, respectively.

4.13. Antibacterial property of hydrogels

To explore the antibacterial activity of Mg²⁺, Quercetin and MgQu, the spread plate experiment was carried out. Specifically, E. coli and S. aureus were selected as a model of inhibited bacteria.Dilute the drug to the corresponding concentration with LB medium, add 10⁶ CFU bacteria to the prepared drug, and use a pipette to draw 100 μ L and drop it into the center of the agar plate. Apply the bacterial solution evenly using a sterilized coating rod, circling clockwise/counterclockwise along the plate until the bacterial solution is completely absorbed and covers the entire agar surface. After being placed upside down in a 37 °C incubator for 14 h, it was taken out and photographed for analysis.

4.14. Wound healing experiment (mice)

BKS-db/db black male mice (SPF grade, 42 days old) were used as experimental subjects, sourced from Saiye (Gu'an) Biotechnology Co., Ltd. The animal research was conducted at Weifang Second People's Hospital (Weifang Respiratory Hospital). These mice exhibit hyperglycemia, with blood glucose levels consistently exceeding 16.65 mmol/L, making them suitable for diabetes-related wound healing studies. A full-thickness wound with a diameter of 6 mm was created on the dorsal skin of the diabetic mice using a sterile scalpel, establishing a dorsal wound model. The wound creation date was designated as Day 0. Post-operative care was administered, and the health of the mice was monitored to prevent complications during the experimental period. After wound establishment in all diabetic mice, the subjects were randomly divided into four groups: the control group, which received no drug treatment; the MgQu group, which received 500 μg of MgQu powder applied uniformly to the wound site; the GelNB/HAMA group, which received 200 μL of blank GelNB/HAMA hydrogel applied to the wound and photopolymerized under ultraviolet light to solidify and adhere to the wound site; and the MgQu@GelNB/HAMA group, which received 500 μg of MgQu dispersed uniformly in 200 μL of GelNB/HAMA, followed by UV irradiation for 30 s to photopolymerize and solidify the hydrogel, adhering it to the wound. Previous research shows that this light exposure time is non-toxic [79]. The hydrogel was preheated to 60 °C to transform from a solid adhesive into a fluid gel, facilitating its application to the wound site and subsequent photopolymerization. Wound photography was performed at days 0, 3, 5, 7, 10, 12, 14, and 16 post-treatment for each group, with regular imaging to monitor healing progression in real-time. ImageJ software was used to quantify healing metrics, analyzing wound closure area, healing rate, and time to complete closure. At Day 3, Day 7 and Day 14 post-treatment, skin samples were excised from each group near the wound site, fixed for 24 h, and subjected to histochemical analysis. The dorsal sections underwent immunohistochemical staining, including H&E, Masson's trichrome, CD31, Col1, and Sirius red staining, along with immunofluorescence staining for macrophage phenotypic characterization.

To further evaluate the in vivo wound-healing efficacy of MgQu and GelNB/HAMA in diabetic mice with skin wounds, photographic documentation was captured for the control and treated groups at days 0, 3, 5, 7, 10, 12, and 14. Wound area was quantified using ImageJ software, and observations were made regarding healing area, healing rate, and time to complete wound closure.

To minimize potential observer bias, all wound images and histological sections were randomly coded before quantitative analysis. Investigators responsible for wound area measurement, histological scoring, and immunofluorescence/immunohistochemical quantification were blinded to the treatment groups. Group information was disclosed only after completion of data analysis.

4.15. Histological staining

The harvested samples were used for Haematoxylin-eosin (H&E), Masson staining, and immunohistochemical (IHC) staining. Initially, the samples were fixed by 4% paraformaldehyde(Beijing Biyuntian Biotechnology Company (China)) and then immersed in 15% EDTA for two weeks. Next, the decalcified samples were dehydrated, followed by gradient ethanol, and embedding in paraffin. For HE, slices were stained by haematoxylin and eosin, respectively. Masson staining was performed following the manufacturer's protocol (Servicebio). IHC staining was performed according to the manufacture's protocol (Daixuan Biotechnology (China)). Images of HE and IHC staining were taken with optical microscope.

4.16. Statistical analysis

Experimental results are presented as mean ± standard deviation (SD). All results presented represent at least three independent experiments. The sample size (n) for each group of figures is detailed. Comparisons between the two groups were analyzed with the unpaired Student's t-test. For group >2, one-way or two-way ANOVA with Bonferroni post hoc test was applied. Statistical analysis was carried out by GraphPad Prism10.1.2 software. Statistical significance is denoted in figures as follows: ns indicates no significance, *p < 0.05, **p < 0.01, ***p < 0.001.

CRediT authorship contribution statement

Yunshu Yang: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. Bin Tang: Data curation, Formal analysis, Investigation. Menghan Zhou: Data curation, Formal analysis, Investigation. Jiayi Sun: Formal analysis. Can Qiu: Data curation, Investigation. Huaman Geng: Data curation, Formal analysis, Investigation. Yajie Wang: Formal analysis, Resources. Yanan Zheng: Formal analysis, Resources. Yujie Hua: Formal analysis, Methodology, Project administration, Visualization. Guanyu Wang: Formal analysis, Methodology. Guangdong Zhou: Funding acquisition, Investigation, Project administration, Supervision. Yingying Huo: Conceptualization, Project administration, Resources. Di Wang: Conceptualization, Funding acquisition, Methodology, Project administration, Writing – review & editing.

Ethics approval and consent to participate

All experiments involving animals were conducted according to the ethical policies and procedures approved by the Animal Care and Experimental Committee (approval number: 2024SDL270). The mice used as experimental subjects were sourced from Saiye (Gu'an) Biotechnology Co., Ltd. The animal research was conducted at Weifang Second People's Hospital (Weifang Respiratory Hospital). This experimental method was carried out in accordance with the "Guidelines for Animal Euthanasia" (2020) published by the American Veterinary Medical Association (AVMA), adheres to veterinary best practice standards, utilizes ether anesthesia and euthanasia methods, considers animal welfare, and complies with widely accepted animal research guidelines.

Declaration of competing interests

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

Acknowledgements

We would like to express our heartfelt gratitude to all participants for their contributions and cooperation. At the same time, we deeply appreciate the meticulous execution and unwavering commitment to the research process by the implementers. Furthermore, We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript. This work was supported by the National Key R&D Program of China (grant number 2024YFA1107800), the Biomaterials and Regenerative Medicine Institute Cooperative Research Project of Shanghai Jiao Tong University School of Medicine (grant number 2022LHA07), the National Natural Science Foundation of China (grant numbers 82302823, 81871502, 82102227, 82472172, and 81671837), the China Postdoctoral Science Foundation (grant number 2023M732303), the Natural Science Foundation of Shandong Province (grant number ZR2024QH057, ZR2026MS1328), the Shandong Province Higher Education Institutions Youth Creative Technology Support Programme (grant number 2024KJJ038), the Weifang science and technology development plan (Grant number: 2024YX034), the Cross Research Fund Project of the Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (grant number JYJC202302).

Footnotes

^{Appendix A}

Supplementary data to this article can be found online at https://doi.org/10.1016/j.mtbio.2026.103547.

Contributor Information

Guangdong Zhou, Email: guangdongzhou@126.com.

Yingying Huo, Email: yingying_huo@shsmu.edu.cn.

Di Wang, Email: wang234di@163.com.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1

mmc1.docx^{(820.6KB, docx)}

Data availability

Data will be made available on request.

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PERMALINK

Phototriggered adhesive hydrogels integrating Mg/Quercetin MOFs for synchronous regulation of inflammation and angiogenesis in diabetic wounds

Yunshu Yang

Bin Tang

Menghan Zhou

Jiayi Sun

Can Qiu

Huaman Geng

Yajie Wang

Yanan Zheng

Yujie Hua

Guanyu Wang

Guangdong Zhou

Yingying Huo

Di Wang

Abstract

Graphical abstract

Highlights

1. Introduction

Fig. 1.

2. Results and discussion

2.1. Preparation and biological evaluation of MgQu

Fig. 2.

2.2. Preparation and mechanical evaluation of MgQu@GelNB/HAMA

Fig. 3.

2.3. MgQu promotes cell migration and angiogenesis

Fig. 4.

2.4. MgQu promotes fibroblast proliferation and collagen production

2.5. MgQu suppressed inflammation and scavenged ROS in vitro

Fig. 5.

2.6. In vitro antibacterial test

2.7. MgQu@GelNB/HAMA promotes diabetic wound healing in vivo

Fig. 6.

2.8. MgQu@GelNB/HAMA regulates the M1/M2 phenotype balance of macrophages in vivo

Fig. 7.

2.9. MgQu@GelNB/HAMA promotes angiogenesis, collagen fiber repair, and tissue regeneration in vivo

Fig. 8.

3. Conclusions

4. Experimental section

4.1. Materials

4.2. Synthesis of metal-organic frameworks

4.3. Fourier transform infrared (FTIR) spectroscope

4.4. Sustained-release experiment

4.5. Release kinetics analysis

4.6. Swelling and enzymatic degradation assessment

4.7. Hemolysis assay

4.8. In vitro biocompatibility testing (CCK-8 and live/dead assay)

4.9. In vitro cell migration and angiogenesis

4.10. EdU incorporation assay

4.11. Estimation of total collagen by hydroxyproline assay

4.12. Detection of ROS generation/anti-inflammatory properties and antioxidant capacity

4.13. Antibacterial property of hydrogels

4.14. Wound healing experiment (mice)

4.15. Histological staining

4.16. Statistical analysis

CRediT authorship contribution statement

Ethics approval and consent to participate

Declaration of competing interests

Acknowledgements

Footnotes

Contributor Information

Appendix A. Supplementary data

Data availability

References

Associated Data

Supplementary Materials

Data Availability Statement

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