A pH-inspired hydrogel enables real-time monitoring and precise treatment of diabetic wounds

Yan Sun; Xiangchen Su; Xinrong Geng; Mengdi Sun; Ge Zhang; Mingzhu Song; Fang Li; Ruizhen Lv; Yuting Zhao; Yijie Shi; Liang Zhao

doi:10.1186/s12951-026-04492-1

. 2026 Apr 29;24:571. doi: 10.1186/s12951-026-04492-1

A pH-inspired hydrogel enables real-time monitoring and precise treatment of diabetic wounds

Yan Sun ^1,^#, Xiangchen Su ^1,^#, Xinrong Geng ^1,^#, Mengdi Sun ^1,^#, Ge Zhang ¹, Mingzhu Song ¹, Fang Li ¹, Ruizhen Lv ¹, Yuting Zhao ¹, Yijie Shi ^1,^2,^✉, Liang Zhao ^1,^2,^3,^✉

PMCID: PMC13274207 PMID: 42057005

Abstract

Diabetic wound healing remains a critical challenge due to a hyperglycemia-driven pathological change and lack of real-time diagnosis and monitoring, leading to delayed interventions and poor outcomes. We designed a pH-responsive multifunctional hydrogel (ZSC-SCHY) by encapsulating Scutellaria baicalensis-derived carbon quantum dots (SRC-CDs) into ZnS nanocages (ZS) within a carboxymethyl chitosan (CMCS)/sodium alginate (SA) hydrogel matrix. In vitro and in vivo evaluation showed that ZSC-SCHY dynamically converted the alkaline wound pH to a weakly acidic state. The pH-responsive fluorescence of SRC-CDs allowed real-time visual monitoring of wounds. Additionally, sustained release of Zn²⁺ and H₂S enhanced deep-tissue penetration and promoted angiogenesis. Notably, ZSC-SCHY significantly enhanced migration, proliferation, and synaptogenesis of Schwann cells, while also supporting endothelial cell functions and tissue remodeling. ZSC-SCHY presented an integrated theranostic platform that simultaneously overcame monitoring deficits and multifactorial pathology in diabetic wounds.

Graphical abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s12951-026-04492-1.

Keywords: Diabetic wounds, Hydrogel, Nanocages, Carbon dots, Schwann cells

Introduction

Diabetic wounds, as one of the most severe complications of diabetes, exhibit a unique pathological microenvironment that significantly impairs wound healing [1–3]. Clinical studies reveal that the characteristic alkaline pH in diabetic wounds not only promotes bacterial proliferation but also compromises host defense mechanisms, substantially increasing the risk of infection [4, 5]. In addition, impaired diabetic wound healing results from a complex interplay of metabolic, vascular, immune, and cellular dysfunctions, all of which hinder the normal processes of tissue repair [6]. Current clinical strategies primarily focus on infection control, anti-inflammatory interventions, and angiogenesis promotion [7]. However, due to the multifactorial pathogenesis of diabetic wounds, these current approaches often yield suboptimal outcomes. The complexity of the wound microenvironment demands the development of novel therapeutic strategies that overcome these interconnected pathological challenges.

The clinical relevance of neuroregeneration in diseases is increasingly supported by previous reports [8, 9]. The widespread neurodysfunction commonly observed in diabetic wounds has been recognized as independent and sensitive predictors of healing outcomes [10]. The underlying mechanism involves high glucose (HG)-induced impairment of cell function and neuropeptide signaling, which damages nerve-driven repair [11]. More importantly, neuroregeneration enhances angiogenesis through neuropeptide release and intercellular communication, guiding macrophages toward a pro-repair phenotype, and accelerating reepithelialization [12]. Therefore, neuroregeneration should be regarded as a core therapeutic target for angiogenesis and inflammation.

Schwann cells (SCs), as glial cells of the peripheral nervous system, serve as crucial facilitators in tissue repair processes. Under normal conditions, SCs transition to a repair phenotype, proliferate, and migrate to the wound area, forming cell columns that guide axon regeneration. At the same time, they secrete neurotrophic factors to promote endothelial cell proliferation and migration, thereby accelerating angiogenesis and tissue repair [13]. However, in a diabetic environment, hyperglycemia significantly impairs their function as evidenced by limited migratory capacity and diminished paracrine activity, ultimately resulting in delayed wound healing [14]. In particular, SCs secrete vascular endothelial growth factor (VEGF) and other pro-angiogenic factors to directly stimulate endothelial cell proliferation and migration. They establish close physical and functional connections with blood vessels, creating a neurovascular network, essential for tissue repair [15]. However, as SCs constitute a relatively small proportion in skin tissues, current therapies struggle to achieve efficient and precise regulation of the functions of SCs. Moreover, the specific biological processes and regulatory mechanisms of SCs in skin regeneration remain unclear, which in turn limits the development of therapeutic strategies and hinders their clinical translation [16].

The integrated visual treatment of diabetic wounds holds significant clinical value by enabling real-time, non-invasive monitoring of wound healing. Fluorescent nanomaterials, such as carbon dots (CDs), allow dynamic tracking of microenvironmental changes, facilitating early detection of infection or delayed healing processes [17, 18]. This approach reduces reliance on biopsies, minimizes patient discomfort, and supports precision treatment by correlating optical signals with therapeutic efficacy [19]. Additionally, CDs combine visual diagnostics with targeted drug delivery, thus accelerating recovery and improving outcomes in chronic diabetic wounds [20]. CDs derived from traditional Chinese medicine (TCM-CDs) are synthesized using active constituents and chemical compounds present in TCM. They are known to not only preserve the medicinal value of the original TCM but also exhibit their excellent optical properties [21]. Particularly, their pH-responsive fluorescence characteristics enable real-time changes in fluorescent signals in response to pH variations in the diabetic wound microenvironment, thereby achieving real-time visual diagnosis of therapeutic efficacy.

Gas therapy utilizes medical gases as therapeutic agents to specifically modulate biological processes, offering non-invasive, targeted treatment for diseases like chronic wounds, cancer, and inflammation [22–24]. On the one hand, therapeutic gases form nanobubbles within wound tissue and create local pressure differences that drive drugs’ movement, enhancing drug delivery to deeper wound layers [25]. On the other hand, these gases regulate oxidative stress, angiogenesis, and immune responses, promoting tissue repair while minimizing systemic side effects [26–28]. Hydrogen sulfide (H₂S) as an important gaseous signaling molecule demonstrates unique advantages in diabetic wound healing as compared to oxygen (O₂) and nitric oxide (NO). H₂S exhibits potent antioxidative properties by scavenging reactive oxygen species (ROS), which are elevated in diabetic wounds. Additionally, H₂S synergistically enhances endothelial function and stimulates vascular growth factors more effectively in impaired diabetic tissues [29]. In particular, H₂S is reported to stimulate SCs proliferation and induce lamellipodia formation, which subsequently facilitates axonal extension and nerve regeneration [30].

To tackle inherent problems in chronic diabetic wound therapies, we proposed a pH-responsive carboxymethyl chitosan/sodium alginate-based hydrogel (ZSC-SCHY), composed of ZnS nanocages (ZS) encapsulating carbon dots (SRC-CDs) derived from the traditional Chinese medicine Scutellaria baicalensis (SRC), for achieving integrated visual diagnosis and treatment. As shown in Fig. 1, SRC-CDs retain partial pharmacological activity of SRC, particularly its potent ROS-scavenging capacity. More importantly, they possess pH-responsive fluorescence transition properties owing to the presence of surface functional groups, thereby providing a visual strategy for monitoring the progression of diabetic wound healing. In the alkaline microenvironment of diabetic wounds, the hydrogel is demonstrated to actively reduce local pH, thereby reversing the pathological microenvironment. Simultaneously, it promotes angiogenesis and reduces inflammation via the synergistic effect of SRC-CDs, Zn²⁺ and H₂S. More importantly, ZSC improves SCs function by regulating the expression of key proteins involved in differentiation and myelination, thus releasing various cytokines and nerve growth factors that promote axonal regeneration. Furthermore, it induces secretion of additional pro-angiogenic factors like VEGF from SCs, thus possibly accelerating the proliferation and migration of vascular endothelial cells. As a result, compared with the untreated diabetic wound, which showed delayed wound healing with a lower rate, ZSC-SCHY significantly accelerated wound healing and increased the healing rate. In summary, this hydrogel is proposed to operate through a synergistic mechanism on pH regulation/real-time visual monitoring/angiogenesis/anti-inflammation/neuroregeneration, providing a theranostic strategy for diabetic chronic wound treatment.

Fig. 1 — (A) Schematic illustration of the synthesis process of ZSC-SCHY. (B) Schematic illustration of ZSC-SCHY for in situ visual monitoring and synergistic therapy of diabetic wounds

Materials and methods

Materials

Carboxymethyl chitosan (CMCS) and N-Hydroxysuccinimide (NHS) were purchased from Shanghai Macklin Biochemical Technology Co., Ltd., Sodium alginate (SA) and n-(3-dimethylaminopropyl)-n’-ethylcarbodiimide hydrochloride (EDC) were purchased from Shandong Keyuan Biochemical Co., Ltd., and Scutellaria baicalensis was purchased from Beijing Tongrentang (Anguo) Traditional Chinese Medicine Pieces Co., Ltd. β-actin (WL01372), myelin basic protein (MBP, WL03919) were procured from WanLeiBio in Shenyang, China. Nuclear factor erythroid 2-related factor 2 (Nrf2, AF0639), Cluster of Differentiation 206 (CD206, DF4149), Inducible nitric oxide synthase (INOS, AF0199), Necrosis Factor alpha (TNF-α, AF7014), Cluster of Differentiation 31 (CD31, AF6191), Interleukin-10 (IL-10, DF6894), Nuclear Factor-kappa B (NF-кB, AF5006), c-Jun (AF6090) were obtained from Affinity in Jiangsu, China. Heme Oxygenase 1 (HO-1, HA721854), Signal Transducer and Activator of Transcription 3 (STAT3, ET1607-38), Vascular endothelial growth factor (VEGF, ET1604-28) antibodies was purchased from Hua’an Biotechnology Co., Ltd. S100B Polyclonal antibody (S100B, 15146-1-AP) and GAP 43 Polyclonal antibody (GAP 43, 16971-1-AP) were obtained from Proteintech in Wuhan, China. The goat anti-rabbit IgG/horseradish peroxidase (HRP) secondary antibody was supplied by EarthOx Life Sciences, located in Millbrae, California, USA. The Sprague Dawley rats obtained from Jinzhou Medical University exhibited a body weight within the range of 180 to 220 g.

Cell culture

Human umbilical vein endothelial cells (HUVECs), Schwann cells (SCs), rat adrenal pheochromocytoma cells (PC12), and mouse monocyte-macrophage leukemia cells (RAW 264.7) were obtained from the Shanghai Cell Bank of the Chinese Academy of Sciences. HUVECs were cultured in F12 medium containing 10% fetal bovine serum (Gibco BRL). High glucose-cultured HUVECs (HG-HUVECs) and SCs (HG-SCs) are typically generated by exposing cells to 40 mM glucose‌ for 72 h in vitro to simulate diabetic conditions with daily medium replacement [31–33]. Inflammatory macrophages were induced by exposure to lipopolysaccharide (LPS) at a concentration of 100 ng/mL for a duration of 24 h [34].

Preparation and characterization of SRC-CDs, ZS, and ZSC

To prepare SRC-CDs, 0.5 g of SRC powder was dissolved in 20 mL of anhydrous ethanol and sonicated for 20 min. The SRC solution was loaded into a reaction vessel and heated at 150 ℃ for 6 h. After centrifugation at 10,000 rpm for 30 min, the supernatant was collected and filtered through a 0.22 μm microporous membrane to obtain SRC-CDs. In order to obtain ZS, 2.38 g of zinc nitrate hexahydrate and 3.93 g of 2-Methylimidazole (2-MeIM) were weighed separately and slowly dissolved in 100 mL of methanol solution under stirring. After stirring for 5 min, the 2-MeIM solution was slowly added dropwise to the stirring zinc nitrate solution using a rubber-tipped pipette. After standing at room temperature for 24 h, the resulting white solid product was centrifuged (6,000 rpm, 3 min), washed with fresh methanol to remove impurities, and the precipitate was collected by centrifugation. Finally, the sample was dried in a vacuum oven at 60 ℃ to prepare ZIF-8. Then, 100 mg of the synthesized ZIF-8 powder and 300 mg of thioacetamide were mixed, ground uniformly, and added to 80 mL of anhydrous ethanol. The mixture was sonicated for 20 min to form a white homogeneous suspension. The prepared solution was slowly added dropwise to a polytetrafluoroethylene liner using a rubber-bulb pipette, and after complete addition, the liner was placed in a stainless steel high-pressure reaction vessel. After completion of the operation, the stainless steel high-pressure reaction vessel was transferred into a hydrothermal chamber and subjected to hydrothermal reaction at 40 °C for 24 h. The product was centrifuged (10,000 rpm, 10 min), washed with deionized water three times, and dried in a vacuum oven at 70 ℃ to obtain ZS. Finally, ZSC was prepared as follows: SRC-CDs and ZS were mixed and stirred for 4 h, followed by ultrasonic treatment for 30 min, and co-incubated for 24 h. After centrifugation (10,000 rpm, 10 min), the supernatant was discarded and ZSC was collected.

The morphology and shape of SRC-CDs, ZS, and ZSC were determined using transmission electron microscope (TEM, Tecnai G2 F20, Hillsborough, OR, USA). The size distributions and zeta-potentials of SRC-CDs, ZS, and ZSC were recorded by a Malvern Zetasizer (Nano ZS, Malvern, UK). The phase structure and crystallinity of SRC-CDs, ZS, and ZSC were identified by X-ray diffraction (XRD, ULTIMAIV RIGAKU, Tokyo, Japan) in the range of 8–80° with a scan rate of 10°/min. The composition and structure of different nanocomposites were detected by X-ray photoelectron spectroscopy (XPS, PHI QUANTERA-II, ULVAC-PHI, INC., Japan). The absorption spectra of samples were analyzed using a UV-vis spectrophotometer (UV-vis, UV-9000, Metash Instruments Co., Ltd, China). The chemical composition of different nanocomposites was characterized by Fourier transform infrared spectroscopy (FT-IR, NICOLET iS10, Thermo Fisher Scientific, USA). Fluorescence spectra were measured using a fluorescence spectrophotometer (Hitachi F-7100, Japan) equipped with a xenon lamp as the excitation source. The elemental composition of ZSC was analyzed using energy dispersive spectroscopy (EDS).

Synthesis and characterization of SCHY and ZSC-SCHY

The preparation process of SCHY and ZSC-SCHY is as follows: CMCS, SA, EDC, and NHS are sequentially added to the containing ZSC solution in specific proportions followed by briefly stirring to achieve homogenization and then allowing to stand at 4 ℃ for static reaction. Finally, ZSC-SCHY containing SRC-CDs at a concentration of 2 mg/g and ZS at a concentration of 0.667 mg/g was obtained by enabling crosslinking to form the hydrogel network structure. By replacing the ZSC solution with ultrapure water and following the same procedure, SCHY is obtained. FTIR spectroscopy was utilized to examine ZSC-SCHY and SCHY, whereas SEM imaging was applied to assess their structural morphology. A rheometer (MCR92, Anton Paar, Austria) was utilized to measure the temperature sweep and angular frequency sweep of ZSC-SCHY and SCHY to evaluate their viscoelastic behavior, and to assess the viscosity changes of ZSC-SCHY and SCHY under shear stress. To evaluate the swelling properties of ZSC-SCHY, samples were immersed in 45 mL of PBS solutions at different pH levels and maintained in sealed vials at 37 °C. ZSC-SCHY was periodically extracted, gently wiped to remove excess surface water, and then weighed. The swelling ratio (SR) was calculated according to the previous report [35]. To assess the degradation rate, dried ZSC-SCHY was soaked in PBS solutions at varying pH levels, kept at a constant 37 °C, and stirred at 100 rpm. Samples were obtained at predetermined temporal intervals, rinsed with deionized water, and then dried at 60 °C for 12 h before weighing. The degradation rate was calculated according to the previous report [36]. To evaluate water retention, ZSC-SCHY and SCHY (10 mm diameter, 5 mm thickness) were placed at room temperature, and their mass (Wₜ) was measured periodically. The water retention rate was calculated as: Water retention rate (%) = (Wₜ/W₀) × 100%, where Wₜ and W₀ represent the hydrogel mass at time t and the initial time, respectively. To investigate in vitro drug release properties, a defined amount of ZSC-SCHY was immersed in 45 mL of PBS solution with different pH values. At predetermined time points, 2 mL of the solution was withdrawn each time and 2 mL of fresh solution was replenished to maintain a constant volume. Finally, the amount of SRC-CDs in the solution was determined using ultraviolet spectroscopy, while the released amount of Zn²⁺ and H₂S were measured via inductively coupled plasma mass spectrometry (ICP-MS) and a micro H₂S detection kit, respectively.

Analysis of the motion behavior of ZS in vitro and in vivo

ZS was co-incubated with Rhodamine B (RhB) for 30 min, and then centrifuged at 10,000 rpm for 30 min. The supernatant was discarded, and the precipitate was washed with PBS, centrifuged, and the precipitate was added to hydrogen peroxide and PBS respectively. The movement trajectory of the particles was photographed using a Leica inverted microscope, and the data was processed by Image J. In order to assess the transdermal release pattern of ZSC-SCHY via nanomotor effects of ZS, RhB was initially loaded onto SRC-CDs-SCHY, ZS-SCHY, and ZSC-SCHY. The RhB-loaded hydrogels were placed at the wound sites of diabetic rats, and after 24 h, the wound tissues were excised and subjected to cryosectioning for observation using a fluorescence microscope (Leica DMI6000B, Germany).

In vitro evaluation of pH visual monitoring

To evaluate the pH detection capability of SRC-CDs, PBS solutions containing SRC-CDs were prepared and adjusted to specified pH levels from 1 to 10. Photographs were taken to document the color changes of SRC-CDs contained solutions under natural light and their fluorescence changes under 365 nm UV irradiation.

In vitro cytocompatibility evaluation

In order to evaluate in vitro cytocompatibility, HUVECs (5 × 10³ cells/well) were seeded in 96-well plates and cultured for 24 h. Subsequently, different concentrations of SRC-CDs (30, 10, 5, 2.5, and 1 µg/mL) and ZS (3, 1, 0.5, 0.25, and 0.1 µg/mL) were respectively co-incubated with HUVECs for 24, 48, and 72 h. Cell viability was determined using Cell Counting Kit-8 (CCK-8), Calcein-AM/PI staining and Tunel assay according to the specified protocol. The hemolytic activity of ZSC was detected through hemolysis assay. First, red blood cells from healthy rats were purified by centrifugation. Then, SRC-CDs, ZS, and ZSC were incubated with 5% red blood cell solution for 1 h, respectively. Red blood cells incubated with H₂O and PBS served as positive and negative controls. After centrifugation, the supernatant was collected, and the absorbance of the supernatant at 540 nm was measured, and the hemolysis rate was calculated according to the previous report [37].

Evaluation of cellular proliferation, migration, and in vitro angiogenesis assay‌

When HG-HUVECs (1 × 10⁴ cells/well) were plated in 24-well plates with SRC-CDs, ZS, or ZSC for 24 h, viability was measured via CCK-8 assay. In the scratch assay, HG-HUVECs and HG-SCs were cultured in 24-well plates, and linear wounds were created using a P200 pipette tip. Following treatment with SRC-CDs, ZS, or ZSC, migration into the wound area was monitored. Gap closure was imaged and quantified using a Leica DMI6000B microscope. For transwell assays, HG-HUVECs and HG-SCs were seeded on 8 μm membranes in chambers containing test agents and incubated at 37 °C with 5% CO₂. Subsequently, cells were fixed in 4% paraformaldehyde and stained with 0.1% crystal violet for 10 min. Finally, the number of cells passing through the membrane was observed and counted using an optical microscope (Leica DMI6000B, Germany).‌ To assess tube formation, HG-HUVECs (1 × 10⁴ cells/well) were suspended in serum-free medium and plated onto Matrigel-coated 24-well plates. After 8-h incubation with SRC-CDs, ZS, or ZSC, the medium was replaced with calcein-containing solution for 30 min. Tubular networks were visualized and quantified via fluorescence microscopy.‌

Assay on secretion of neurotrophic factors and axon outgrowth of PC12 cells

HG-SCs cultured medium (SCM (HG)) was collected to assess the secretion of neurotrophic factors. Briefly, HG-SCs (1 × 10⁴ cells/well) were plated in 24-well plates. Following 24-h incubation, the medium was replaced with 5 mL fresh medium containing SRC-CDs, ZS, and ZSC. After another 24-h incubation, SCM (HG) was collected and subjected to high-speed centrifugation (10,000 × g, 30 min) followed by filtration through a 0.22 μm membrane to ensure the supernatant was free of residual particles. The concentrations of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in SCM (HG) were measured using enzyme-linked immunosorbent assay (ELISA) kits. HG-PC12 cells were seeded in 24-well plates at a density of 1 × 10⁴ cells/mL. After 24 h of incubation, the medium was carefully replaced with 5 mL of SCM (HG) or culture medium of HG-SCs treated with ZSC (SCM (HG + ZSC)) for 24 h. Subsequently, HG-PC12 cells were incubated for another 24 h to observe morphological changes.

Establishment of type 1 diabetic rat skin wounds and theranostic intervention

To establish a type 1 diabetic rat model, Sprague-Dawley rats (7–8 weeks) provided by Jinzhou Medical University were treated with intraperitoneal streptozotocin (STZ, Sigma, Germany) injection (blood glucose > 16.7 mmol/L). All in vivo experiments were conducted with three animals per group. Following anesthesia and dorsal shaving, circular skin wounds (20 mm in diameter) were excised. Diabetic wounds were covered with daily administration of SCHY and ZSC-SCHY for 14 days. Each rat was housed individually in separate cages and closely monitored throughout the period. On day 3, wound exudate was sampled with sterile swabs followed by continuous shaking culture in bacterial growth medium at 220 rpm for 3 h. Finally, after 24 h of plating on agar plates, colony numbers were determined by visual inspection. Wound closure was quantified by image analysis. Tissue samples underwent formalin fixation, paraffin embedding, and sectioning. Bacterial infiltration was assessed via Giemsa staining, while Hematoxylin and Eosin (H&E) stain and Masson trichrome stain were used to evaluate histopathology and collagen deposition, respectively.‌ Immunohistochemical (IHC) staining was used to detect CD31 expression, and immunofluorescence staining was used to detect the expression of DHE, INOS, CD206, TNF-α, IL-10, GAP-43, and S100B. In terms of visual inspection of diabetic wounds in vivo, the pH value of wound exudate was measured using pH test paper to detect the changes in pH at the wound site before and after administration. Additionally, to evaluate the visual monitoring capability of wound dressings at wound sites, ZSC-SCHY was applied to diabetic wounds in different treatment groups, and photographs were taken at regular intervals.

IHC staining assay

After treatment of dewaxing in xylene, graded alcohol rehydration, and endogenous peroxidase inactivation with 3% hydrogen peroxide (10 min), antigen retrieval was performed using citrate buffer (pH 6.0, 3 min), followed by PBS washing, blocking with goat serum (20 min), and overnight incubation with primary antibodies at 4 °C.‌ Following this, tissue sections underwent immunodetection using polymer-based systems and species-specific immunoglobulin (IgG) conjugates, followed by 3,3′-diaminobenzidine (DAB) chromogenic visualization. Hematoxylin was used as a counterstain to highlight tissue morphology. The stained sections were then dehydrated, cleared, and mounted on glass slides with a suitable mounting medium, like resin, to ensure the longevity of the stain and to protect the tissue. IHC slides were imaged using a Leica DMI6000B microscope for analysis. Negative controls, processed with normal serum instead of primary antibodies, were included to assess non-specific binding. Staining intensity was quantified via optical microscopy with integrated image analysis software.‌

Immunofluorescence staining

Tissue specimens were initially fixed in appropriate fixative containing 4% paraformaldehyde for 30 min. After fixation, permeabilization was performed using 0.1% Triton X-100, which facilitates antibody penetration through cell membranes to interact with intracellular antigens. Following incubation in goat serum for 20 min to exclude non-specific binding, samples were treated with primary antibodies targeting the desired antigens. Secondary antibodies conjugated with fluorescent dyes were then incubated, which bind to the primary antibodies, enabling detection of target antigens. For visualization, fluorescent images were captured using a fluorescence microscope (Leica DMI6000B, Germany).

Western blot analysis

Cells from different treatments were scraped using cell scrapers, then lysed in lysis buffer, followed by centrifugation (12,000 rpm, 4 °C, 30 min). The supernatant was used for protein concentration determination. Next, protein samples from different groups were electrophoresed on SDS-PAGE and transferred to PVDF membranes.‌ PVDF membranes were then blocked with 0.1% bovine serum albumin (BSA) at room temperature for 2 h, followed by incubation with primary antibodies at 4 °C in a dark chamber for 16–20 h. Secondary antibodies labeled with HRP were incubated with primary antibodies at room temperature for 2 h. When performing enhanced chemiluminescence (ECL) staining, membrane images were captured and further analyzed for protein band intensity.

Statistical analysis

All graph plotting and data analysis were performed by software, respectively. All experiments were conducted at least three times, and all data were expressed as mean ± SD. T-test was used to test for significant differences between two groups of data, and one-way analysis of variance (ANOVA) was used to test for significant differences between multiple groups of data. Graphs display statistical significance as follows: ^*p < 0.05, ^**p < 0.01, ^***p < 0.001.

Results

Characterization of SRC-CDs, ZS, and ZSC

SRC-CDs were synthesized through one-step solvothermal treatment in ethanol, while ZS was prepared using low-temperature thermal sulfidation. TEM was employed to observe the morphology and size distribution of the synthesized SRC-CDs, ZS, and ZSC. As shown in Fig. 2 A, SRC-CDs exhibited a monodispersed approximately spherical structure with a small particle size of approximately 9 nm. TEM images confirmed the dodecahedral hollow nanocage structure of ZS and ZSC, with ZSC displaying a larger particle size. Dynamic light scattering (DLS) measurements further characterized the particle size and zeta potential of SRC-CDs, ZS, and ZSC, with results showing particle sizes of approximately 9 nm, 403 nm, and 426 nm, respectively (Fig. 2B). Zeta potential analysis revealed values of −3.6 mV, −12.5 mV, and −4.1 mV for SRC-CDs, ZS, and ZSC, respectively (Fig. 2D). We systematically evaluated the physicochemical stability of SRC-CDs, ZS, and ZSC over 7 days under simulated conditions with different pH. As shown in Figure S1, they exhibited good stability and no significant changes were observed in the hydrodynamic diameter, polydispersity index (PDI) and Zeta potential of SRC-CDs, ZS, and ZSC under the tested pH conditions, further confirming the excellent stability of these materials. Elemental mapping of ZSC (Fig. 2 C) showed uniform distribution of multiple elements including C, N, O, S, and Zn, indicating that SRC-CDs were uniformly encapsulated within and on the surface of ZS. According to XRD results (Fig. 2E), it was found that the diffraction peaks of ZSC were nearly identical to those of ZS, but its peak intensity had changed, suggesting that loading SRC-CDs into ZS may affect their crystal structure. Additionally, FTIR was used to confirm elemental composition and surface structure. As shown in Fig. 2 F, FTIR spectra of SRC-CDs exhibited O-H, N-H, -COO⁻, C = N, and C-O/N vibration peaks at 3362 cm⁻¹, 3062 cm⁻¹, 1618 cm⁻¹, 1502 cm⁻¹, and 1367–1050 cm⁻¹, respectively, indicating the presence of abundant oxygen- and nitrogen-containing functional groups on the SRC-CDs, while ZS and ZSC exhibited characteristic peaks at 600–1500 cm⁻¹, corresponding to Zn-N bond and imidazole ring vibrations, respectively. Furthermore, after loading SRC-CDs into ZS, most characteristic peaks of SRC-CDs were masked by ZS, but unique C = O and C = N characteristic peaks belonging to SRC-CDs could still be observed in the ZSC spectrum. UV spectra showed that the absorption peak of ZS was located at approximately 220 nm, while the absorption peaks of SRC-CDs were located at approximately 220 nm and 344 nm, respectively. The absorption spectrum of ZSC exhibited both the absorption characteristics of ZS and SRC-CDs, which demonstrated the successful preparation of ZSC (Figure S2). Subsequently, XPS was used to detect the elemental composition and valence states of SRC-CDs, ZS, and ZSC. As shown in Fig. 2G, XPS survey spectra confirmed the presence of C, N, O, Zn, and S in ZSC, indicating successful encapsulation of SRC-CDs in ZSC. As shown in Fig. 2H, the Zn 2p spectrum of ZSC appeared at 1021.7 eV (Zn 2p₃/₂) and 1044.4 eV (Zn 2p₁/₂). As illustrated in Figure S3, the high-resolution C 1 s spectrum of ZS shows peaks at 284.8 eV, 286.1 eV, and 287.1 eV, corresponding to C-C/C = C bonds, C-N bonds, and C = N bonds, respectively. Compared with ZS, ZSC displays enhanced intensity at these three peaks, which can be attributed to the coordination between carboxyl groups in SRC-CDs and Zn²⁺ in ZS. The high-resolution N 1 s spectrum of ZSC shows peaks at 398.6 eV and 399.5 eV, corresponding to C = N and C-N bonds, respectively. Relative to ZS, the changes in peak intensity and binding energy shifts of these N 1 s peaks in ZSC indicate that nitrogen-containing groups in SRC-CDs can also coordinate with Zn²⁺ in ZS. These results confirm the strong interfacial interaction between ZS and SRC-CDs. Finally, it was found that the encapsulation efficiency of SRC-CDs in ZSC was determined to be 56.6%, and the loading efficiency of SRC-CDs in ZSC was 36.1%.

Fig. 2 — (A) TEM image and size distribution histograms of SRC-CDs, ZS, and ZSC. The scale bar for SRC-CDs is 50 nm, and the scale bars for ZS and ZSC are 200 nm. (B) Particle size distribution of SRC-CDs, ZS, and ZSC measured by DLS (n = 3). (C) Elemental mapping of ZSC (n = 3). The scale bar is 100 nm. (D) Zeta potential of SRC-CDs, ZS, and ZSC measured by Zetasizer Nano ZS (n = 3). (E) XRD patterns of SRC-CDs, ZS, and ZSC. (F) FTIR spectra of SRC-CDs, ZS, and ZSC. (G) XPS survey spectra of SRC-CDs, ZS, and ZSC, and (H) Zn 2p of ZS and ZSC. (I) Trajectories of ZS in medium containing 0 µM H₂O₂ and 50 µM H₂O₂ conditions (n = 3). (J) MSD of ZS in medium containing 0 µM H₂O₂ and 50 µM H₂O₂ (n = 3). (K) Translational speed of ZS in medium containing 0 µM H₂O₂ and 50 µM H₂O₂. The data are expressed as the mean ± SD (n = 3), ^***p < 0.001. (L) Gas images generated by ZS and ZSC in medium containing 0 µM H₂O₂ and 50 µM H₂O₂ (n = 3). (M) H₂S release from ZS and ZSC in the presence of H₂O₂ or not. The data are expressed as the mean ± SD (n = 3), ^***p < 0.001. (N) Images of distribution of RhB in diabetic wound coverings at 24 h in RhB loaded SRC-CDs-SCHY, RhB loaded ZS-SCHY, RhB loaded ZSC-SCHY treated groups. The scale bar is 500 μm

The diabetic wound microenvironment is characterized by hyperglycemia, hypoxia, and elevated levels of ROS [38, 39]. Studies have shown that H₂O₂ is the predominant component of ROS in wounds and is present at a steady-state micromolar concentration in wound fluid. In diabetic rat wound models, the local H₂O₂ concentration typically ranges from 10 µM to 100 µM [40]. Based on this, to directly assess whether this physiological concentration is sufficient to propel our designed ZS, we simulated an in vitro environment containing 50 µM H₂O₂ and recorded their motion trajectories using optical video (30 frames/second) to evaluate their autonomous propulsion capability. Results (Fig. 2I, J and K) demonstrated that H₂O₂ could trigger gas generation in ZS, significantly enhancing its motion capability, manifested as higher motion velocity and longer mean square displacement (MSD). In contrast, ZS only exhibited typical Brownian motion with lower motion velocity and MSD in the absence of H₂O₂. This finding indicated that ZS can function as a nanomotor in the presence of H₂O₂, possessing the potential to propel drugs toward deeper wound tissues. We further explored nanomotor effects of ZSC and SRC-CDs in the presence of H₂O₂. The results (Figure S4) clearly showed that SRC-CDs only showed Brownian motion without any sign of directional motion or diffusion enhancement. By contrast, ZSC exhibited significant motor behavior, which is characterized by higher motion speed and larger mean square displacement. It confirmed that nanomotor activity of ZSC originated specifically from ZS. To further validate gas generation, we observed bubble formation in ZS and ZSC solutions with/without the addition of H₂O₂. The results showed that in the presence of H₂O₂, a large amount of gas was generated from ZS and ZSC, consistent with the nanomotor analysis results (Fig. 2L). To further confirm the generation of H₂S gas, we employed a characteristic chemical reaction for verification. As shown in Figure S5, when the gas was introduced into a copper sulfate solution, the formation of a black precipitate was observed. It is because of the reaction between Cu²⁺ and H₂S, producing CuS precipitate, which serves as characteristic evidence for the identification of H₂S. The release of H₂S from ZS and ZSC upon H₂O₂ stimulation was further quantified using a micro H₂S detection kit. The results (Fig. 2M) demonstrate that both ZSC and ZS can effectively generate H₂S gas in the presence of H₂O₂, and this gas can function as a gas motor as well as exert therapeutic effects. Finally, we validated the nanomotor effect of ZS in a diabetic rat wound model. As shown in Fig. 2 N, RhB-labeled ZS-loaded SCHY (ZS-SCHY) and ZSC-SCHY exhibited deeper red fluorescence penetration into wound sites as compared to SRC-CDs-SCHY (lacking ZS), suggesting enhanced drug delivery to dermal layers. This effect likely stems from ZS-mediated H₂S nanomotor activity within ZS-loaded hydrogels, facilitating deeper skin penetration and therapeutic efficacy.‌.

The pH-responsive fluorescence characteristics of SRC-CDs

To verify the pH-responsive fluorescence transition properties of SRC-CDs prepared by the solvothermal method, a series of spectroscopic analyses were performed to clarify their potential as intelligent pH-responsive fluorescent probes. Firstly, SRC-CDs exhibit excellent optical properties. As shown in Fig. 3 A, the optimal excitation wavelength (EX) of SRC-CDs is 470 nm, and the emission wavelength (EM) is 570 nm. They emit bright yellow fluorescence under 365 nm UV irradiation. We further investigated the three-dimensional fluorescence emission spectra of SRC-CDs at different excitation wavelengths ranging from 200 to 900 nm. The results (Fig. 3B) showed that the fluorescence intensity of the synthesized SRC-CDs first increased and then decreased as the excitation wavelength increased. This phenomenon can be attributed to the quantum size effect and the diversity of surface emissive sites on SRC-CDs. Given that the fluorescent stability and intensity of CDs are crucial for biological applications, we further analyzed the fluorescence intensity of SRC-CDs under different pH to evaluate their fluorescence stability. As shown in Fig. 3 C, the fluorescence intensity of SRC-CDs exhibited significant changes at different pH values. Under acidic conditions (low pH), the oxygen-containing functional groups such as carboxyl -COOH and hydroxyl -OH on the surface of SRC-CDs tended to undergo protonation (e.g., -COOH → -COOH₂⁺ or -OH→-OH₂⁺), which reduces non-radiative transitions or suppresses charge transfer, thereby enhancing fluorescence. Additionally, protonation may decrease the electrostatic repulsion between functional groups, resulting in a more stable SRC-CDs structure and reducing fluorescence quenching caused by surface defects. In contrast, the fluorescence intensity of SRC-CDs decreases in alkaline environments as the pH increases. This may be attributed to the deprotonation of oxygen-containing groups such as carboxyl groups, which affects the non-radiative transition processes competing with the luminescence process, thereby quenching the fluorescence of the SRC-CDs. The fluorescence intensity of SRC-CDs dynamically adjusts with changes in pH, demonstrating pH-dependent fluorescence behavior and a regular relationship between fluorescence intensity and pH value. This property enables real-time monitoring of the alkaline microenvironment characteristic of diabetic wounds. As shown in Fig. 3D, the fluorescence intensity of SRC-CDs also varies with excitation wavelength, indicating wavelength-dependent fluorescence characteristics, with the strongest fluorescence observed at a specific excitation wavelength (470 nm excitation for SRC-CDs). To evaluate potential interference from a range of biological analytes, we monitored the fluorescence changes of SRC-CDs in the presence of various essential metal ions under physiological conditions (37 ℃, pH 7.4) (Fig. 3E). Encouragingly, no significant deviations were observed in the fluorescence spectra of SRC-CDs even in the presence of these putative biological interferents such as NaCl and KCl, rendering them highly attractive for applications in diabetic wound treatment. For dynamic monitoring of the pH changes in diabetic wounds, ideal pH-responsive CDs should be capable of real-time, reversible pH measurement. To evaluate the reversibility of SRC-CDs in pH sensing, we examined the changes in their fluorescence properties during cyclic regulation of pH values between 8 and 6. As illustrated in Fig. 3 F, the fluorescence intensity of SRC-CDs remained well-maintained after six cycles of switching between pH 6 and pH 8, indicating excellent fluorescence stability.

Fig. 3 — (A) Optimal excitation (EX = 470 nm) and emission spectra (EM = 570 nm) of SRC-CDs. (Inset images: the images of SRC-CDs under brightfield (left) and 365 nm UV illumination (right). (B) 3D fluorescence spectra of SRC-CDs. (C) The fluorescence emission spectra of SRC-CDs at different pH values (EX = 470 nm). (D) Fluorescence emission spectra of SRC-CDs under different excitation wavelengths. (E) Fluorescence changes of SRC-CDs in the presence of different biological interferents. (F) The fluorescence intensity of SRC-CDs after six cycles in different pH solutions. (G) The fluorescence intensity of SRC-CDs across various time periods. (H) Colorimetric images of SRC-CDs solutions at different pH values with corresponding RGB channel separation

To investigate the fluorescence stability of SRC-CDs in solutions, we monitored their fluorescence changes over a 3-h period. The results indicated that SRC-CDs exhibit high fluorescence stability under these conditions, supporting their suitability for bioimaging applications (Fig. 3G). To visually assess the color change resulting from the pH-responsive fluorescence properties of SRC-CDs, we exposed solutions with varying pH values under natural light and 365 nm UV irradiation. According to Figure S6, the color of SRC-CDs solution changes with the variation of pH value, which further proves that SRC-CDs have great potential in real-time monitoring of pH changes. Through the dynamic change and superposition effect of the three primary colors (red [R], green [G], and blue [B]), a variety of colors can be generated and adjusted. To solve the inherent subjectivity and inaccuracy of visual color discrimination, smartphones was used to collect images, converts visual colors into corresponding RGB channel values, and then constructs a quantitative correlation model between pH value and RGB parameters, thereby realizing the accurate determination of the pH value at wound site. As shown in Fig. 3H, SRC-CDs exhibited significant color response characteristics in the pH range of 1–10. After decomposing its color information into RGB channel signals, it was found that the R, G, and B channel values of SRC-CDs change with pH value, with the B channel showing the most obvious change. Meanwhile, there is a good linear relationship between the fluorescence intensity of SRC-CDs and pH value (Figure S7), indicating that SRC-CDs can be used as a visual pH sensing material for practical scenarios and on-site monitoring. The clinically critical window for wound healing lies between pH 6.0 and 8.5. Diabetic wounds typically exhibit an alkaline microenvironment (≈ 7.5–8.5), while normal healing progresses in a weakly acidic milieu (≈ 6.0–7.0). Therefore, we focused on measuring pH in vitro across the clinically relevant wound pH range (6.0–8.5). Within this range (6.0–8.5), the fluorescence intensity of SRC-CDs decreases linearly with increasing pH and exhibits reversible responsiveness, making it suitable for wound microenvironment monitoring. Based on this, we integrated smartphone-based visual analysis by capturing fluorescence images of the hydrogel at the wound site and extracting RGB values, achieving intuitive, semi-quantitative pH detection within the 6.0–8.5 range and providing a convenient visual tool for clinical wound care.

The physical characterization and adhesive properties of ZSC-SCHY

As the physical characterization and adhesive properties of hydrogels at diabetic wound sites are critical factors influencing their therapeutic efficacy, parameters such as morphological characteristics, swelling capacity, degradation behavior, rheological properties, and interfacial adhesion were determined in vitro. SEM images (Fig. 4 A) revealed a porous three-dimensional structure in the SCHY, and a marked reduction in pore size was observed in the ZSC-SCHY. EDS analysis of the ZSC-SCHY confirmed the presence of C, N, O, Zn, and S, further verifying the uniform distribution of ZSC within the hydrogel (Fig. 4B). As adhesion is crucial for wound closure and preventing slippage, we investigated the adhesive behavior of ZSC-SCHY on several common materials. ZSC-SCHY exhibited excellent adhesive performance on various hydrophilic and hydrophobic substrates including glass, plastic, paper, and iron (Fig. 4 C). Furthermore, when ZSC-SCHY adhered to the skin, it demonstrated superior adhesion and flexibility even under bending or stretching of finger joints, indicating that ZSC-SCHY has the potential to serve as an adhesive wound dressing (Fig. 4D). Rheological evaluation (Figure S8) shows that the storage modulus (G’) and loss modulus (G”) of SCHY and ZSC-SCHY exhibit significant stability in the temperature range of 25–45°C, highlighting a robust and uniform internal gel structure. Such stability is crucial for maintaining performance under different environmental conditions. At 37 °C, both ZSC-SCHY and SCHY maintained storage modulus (G’) that consistently exceeded loss modulus (G”) as angular frequency gradually increased (Fig. 4E). This behavior reflects the dynamic and elastic properties of the ZSC-SCHY and SCHY networks. Both SCHY and ZSC-SCHY exhibited shear-thinning behavior, with viscosity markedly decreasing at elevated shear rates and recovering upon shear reduction. This reversible rheological response showed their suitability as adaptive wound dressings capable of conforming to dynamic tissue environments‌ (Fig. 4 F).

FTIR spectroscopy (Fig. 4G) confirmed the successful synthesis of SCHY and ZSC-SCHY, evidenced by characteristic hydrogen and amide bond formation.‌ Based on the structural formulas of CMCS and SA, the absorption peaks of CMCS and SA in the range of 1500–1650 cm⁻¹ correspond to the stretching vibration of C = O in their structures. The absorption peaks of SCHY and ZSC-SCHY at 1623 cm⁻¹ indicate the presence of the amide I band (C = O), while the weak absorption peaks observed at 1420 cm⁻¹ for both confirm the formation of the amide II band (C-N-H). Additionally, SCHY and ZSC-SCHY exhibit characteristic peaks near 1270 cm⁻¹ corresponding to C-N vibrations, thereby verifying the existence of the amide III band (involving C-N stretching vibration). The asymmetric stretching vibration peak of C = O in carboxylate (-COO⁻) was around 1623 cm⁻¹, where the characteristic peak -COO⁻ in SA was at 1609 cm⁻¹, and the characteristic peak of CMCS was at 1596 cm⁻¹. After preparing the hydrogel, the characteristic peak shifted to 1623 cm⁻¹, indicating that CMCS and SA underwent crosslinking reactions, leading to peak position changes. The observed C-N stretching vibration peak or carboxylate group symmetric vibration peak at 1420 cm⁻¹ exhibited changes in peak intensity following crosslinking, further verifying the induction of these amide reactions. Meanwhile, FTIR spectroscopy was performed on the physical mixture of SA and CMCS (SA-CMCS) without the addition of EDC/NHS. The results showed that the peak intensities of SA-CMCS in the characteristic amide regions (around 1623 cm⁻¹ and around 1420 cm⁻¹) were significantly lower than those of SCHY sample prepared using EDC/NHS. It indicates that as the physical mixture relies solely on non-covalent interactions such as electrostatic attraction, hydrogen bonding, and chain entanglement, the formation of new covalent amide bonds is minimal, resulting in a weak corresponding infrared absorption. In contrast, the addition of EDC/NHS effectively catalyzes the dehydration-condensation reaction between carboxyl and amino groups, generating a large number of covalent amide bonds, which leads to a significant enhancement of the characteristic amide absorption peaks in the infrared spectrum, confirming the successful realization of chemical cross-linking. The XPS results (Figure S9) showed that compared with SA-CMCS, the N 1 s spectrum of SCHY induced by crosslinking reaction involving EDC/NHS exhibited more formation of amide nitrogen as evidenced by higher peak area at approximately 400.2 eV, attributed to the N-C = O structure. It collectively verified the successful construction of a covalent crosslinked network between the carboxyl groups of CMCS and the amino groups of SA via EDC/NHS. To investigate the hydrolysis behavior of amide bonds in a weakly alkaline environment, the prepared hydrogel was subjected to hydrolysis in a weak alkaline solution (pH = 8.3). FTIR results further confirmed that in the mildly alkaline microenvironment, the amide bonds undergo hydrolysis and cleave into free –COOH and –NH₂ groups. The released carboxyl groups (–COOH), being weakly acidic, ionize to release H⁺. This gradually lowers the local pH, ultimately shifting the wound microenvironment from alkaline to weakly acidic. To further verify the pH regulation ability of SCHY and ZSC-SCHY, they were incubated in PBS (pH 8.3), where the pH of solution gradually decreased to 6.9 over 24 h (Fig. 4H). The results showed that ZSC-SCHY effectively modulates local pH, converting weakly alkaline conditions to mildly acidic, thereby promoting wound healing process.‌ Swelling ability is a key hydrogel property, essential for exudate absorption and wound moisture retention.‌ To verify the swelling properties of this hydrogel, we placed the hydrogel in PBS solutions with different pH values. As shown in Fig. 4I, the swelling rate of ZSC-SCHY in an alkaline environment (pH = 8.3) was higher with increase of incubation time, reaching approximately 131.42% after 12 h of treatment, indicating that ZSC-SCHY exhibits rapid exudate absorption capabilities, creating a moist microenvironment that facilitates wound epithelialization and granulation tissue formation. The swelling property of hydrogel was further evaluated under simulated wound fluid conditions. Based on the previous report [41], ZSC-SCHY was implanted in the dorsal wound of diabetic rats and sutured. After implantation, ZSC-SCHY was infiltrated by the body fluid at the wound. The swelling ratio was calculated by taking out the implanted ZSC-SCHY at different predetermined time points and measuring its weight change. The results (Figure S10) showed that ZSC-SCHY maintains a high swelling ratio within 12 h under complex in vivo conditions, and its swelling ratio is as high as 80%, which indicated that it has good swelling performance. Additionally, ZSC-SCHY exhibited gradual and sustained degradation (Fig. 4 J). Consequently, in vitro drug release profiles were evaluated under simulated alkaline wound conditions. Results demonstrated a sustained release of SRC-CDs from ZSC-SCHY over 72 h (Fig. 4 K). Meanwhile, as shown in Figure S11, Zn²⁺ showed a sustained release trend over 48 h, with a cumulative release rate of approximately 30%. The cumulative release amount of H₂S reached about 0.24 mM. It suggested that the initial rapid release and subsequent slow release of the drug from ZSC-SCHY is primarily controlled by diffusion. ZSC located on or near the gel surface have extremely short diffusion paths and can quickly enter the external medium, resulting in a burst release effect. At the start of release, the concentration difference of the drug between the interior of the gel and the external medium is maximal, providing the strongest driving force for diffusion. The released ZS further undergo chemical reactions, rapidly generating and releasing more amount of Zn²⁺ and H₂S. As release proceeds, ZSC from the interior must travel through longer gel network paths to reach the surface and internal ZSC concentration within the gel gradually decreases, leading to subsequent slow release. Since a moist environment plays a crucial role in diabetic wound healing, such as promoting cell proliferation and migration, angiogenesis, and reducing scar formation, we conducted relevant experiments on the moisturizing properties of ZSC-SCHY. The results showed that the hydrogel maintained a water content of approximately 40% after 24 h under sunlight, demonstrating good moisturizing performance (Fig. 4L).

ZSC induced angiogenesis and M1/M2 transition of macrophage

To investigate whether SRC-CDs, ZS, and their combination ZSC promote proliferation and angiogenesis in cells under HG stimulation, CCK-8 assays, scratch assays, transwell assays, proliferation assays, and tube formation assays were performed. An osmotic control using mannitol was included to exclude HG-induced hyperosmotic effects. The results (Figure S12) showed that, compared with the normal HUVECs (control group), treatment with 40 mM mannitol which matches the osmotic pressure induced by 40 mM HG did not induce significant changes in cell viability as measured by the CCK-8 assay. Furthermore, no significant increase in intracellular ROS levels was observed in the mannitol-treated group. These findings indicate that the effects observed in the following investigation can be specifically attributed to HG stimulation rather than to the effects of high osmotic pressure. The results (Figure S13 and S14) indicate that SRC-CDs at 10 µg/mL and ZS at 0.1 µg/mL exhibited the highest cell viability and induced no cytotoxicity within 72 h. The live/dead fluorescence staining results (Figure S15) showed that treatment with SRC-CDs, ZS, and ZSC did not compromise cell membrane integrity, with no significant difference in the proportion of live cells as compared to untreated normal HUVECs (control group) within 72 h. Furthermore, TUNEL apoptosis assays (Figure S16) confirmed that the treatment of SRC-CDs, ZS, and ZSC did not induce apoptosis of cells. Taken together, all results confirmed the excellent compatibility and safety of SRC-CDs, ZS, and ZSC. Next, we proceeded to evaluate the pro-angiogenic effects of ZSC under HG conditions. As shown in Figure S17 and Fig. 5 A, B, C, D, E and F, the CCK-8 cell proliferation assay additionally confirmed that HG induction resulted in cell viability below 75%. HG treatment suppressed angiogenic activity of HUVECs, evidenced by impaired migration capacity, diminished basement membrane penetration capacity, and reduced tube formation. In contrast, treatment with SRC-CDs, ZS, or ZSC markedly promoted angiogenesis, exhibiting higher cell viability, a faster cell migration rate, enhanced basement membrane penetration and more tube formation observed as compared to untreated HG-HUVECs group. Owing to the combined properties of SRC-CDs and the Zn²⁺/H₂S, ZSC resulted in optimal angiogenic outcomes, exhibiting the highest cell viability, accelerated migration, maximal basement membrane penetration, and most tube formation among all treatment groups.

Fig. 5 — (A) Cell scratch images in HG-HUVECs treated with SRC-CDs, ZS, and ZSC at 24 h and 48 h (n = 3). The scale bar is 500 μm. (B) The migration levels of HG-HUVECs cells at 24 h and 48 h among different treatment groups. The data are expressed as the mean ± SD (n = 3), ^***p < 0.001. (C) Migration pictures of HG-HUVECs treated with SRC-CDs, ZS, and ZSC (n = 3). The scale bar is 100 μm. (D) Quantitative analysis of number of migratory HG-HUVECs treated with SRC-CDs, ZS, and ZSC. The data are expressed as the mean ± SD (n = 3), ^***p < 0.001. (E) In vitro images of tube formation in HG-HUVECs following treatment with SRC-CDs, ZS, and ZSC (n = 3). The scale bar is 200 μm. (F) Quantitative analysis of number of tube formation in HG-HUVECs treated with SRC-CDs, ZS, and ZSC. The data are expressed as the mean ± SD (n = 3), ^**p < 0.01, ^***p < 0.001. (G) Fluorescence images of DCF in HG-HUVECs treated with SRC-CDs, ZS, and ZSC (n = 3). The scale bar is 100 μm. (H) Relative fluorescence intensity of DCF in HG-HUVECs treated with SRC-CDs, ZS, and ZSC. The data are expressed as the mean ± SD (n = 3), ^***p < 0.001. (I) Immunofluorescence images of INOS in LPS-RAW 264.7 cells treated with SRC-CDs, ZS, and ZSC for 24 h (n = 3). The scale bar is 100 μm. (J) Relative fluorescence intensity of INOS in LPS-RAW 264.7 cells treated with SRC-CDs, ZS, and ZSC for 24 h. The data are expressed as the mean ± SD (n = 3), ^**p < 0.01, ^***p < 0.001. (K) Immunofluorescence images of CD206 in LPS-RAW 264.7 cells treated with SRC-CDs, ZS, and ZSC for 24 h (n = 3). The scale bar is 100 μm. (L) Relative fluorescence intensity of CD206 in LPS-RAW 264.7 cells treated with SRC-CDs, ZS, and ZSC for 24 h. The data are expressed as the mean ± SD (n = 3), ^**p < 0.01, ^***p < 0.001. (M) Western blot images of Nrf2 and VEGF in HG-HUVECs treated with SRC-CDs, ZS, and ZSC (n = 3). (N) Western blot images of NF-кB, HO-1, and STAT3 in LPS-RAW 264.7 treated with SRC-CDs, ZS, and ZSC (n = 3)

To investigate the ROS scavenging ability of SRC-CDs, ZS, and ZSC, we assessed antioxidant activity by quantifying ROS alterations in HG-HUVECs using DCF probes. As shown in Fig. 5G and H, ROS levels were significantly higher in HG-HUVECs than those in normal HUVECs (control group), indicating that HG induced elevated ROS production. In contrast, treatment with ZS, SRC-CDs, and ZSC reduced ROS levels. In particular, ZSC group exhibited the lowest ROS levels. These results confirmed that the increased ROS levels were successfully attenuated after using ZSC. It has been reported that SRC-CDs synergistically activate VEGF signaling by reducing oxidative stress and preserving VEGF signaling in endothelial cells [42]‌. Zn²⁺ stabilizes intracellular redox balance, reducing oxidative stress in endothelial cells under hypoxia, which indirectly preserves VEGF expression [43]. H₂S, as a signaling molecule, directly binds to ‌VEGF‌, promoting endothelial cell migration and tube formation [44]. The Western blot results (Fig. 5M and S18) revealed that Nrf2 protein was significantly upregulated after ZSC treatment, indicating successful activation of the Nrf2 pathway, which effectively alleviated oxidative stress. Furthermore, the expression level of VEGF in the ZSC-treated group were significantly higher than that in the untreated HG-HUVECs group. ZSC promotes angiogenesis by enhancing VEGF expression, improving endothelial function, and creating an optimal microenvironment for vascular growth through antioxidant, and pro-angiogenic mechanisms.

To further investigate the anti-inflammatory properties of ZSC, we examined its effects on M1/M2 phenotype-related protein expression in RAW 264.7 cells stimulated with LPS. Immunofluorescence results (Fig. 5I, J, K and L) showed that SRC-CDs, ZS, and ZSC treatment led to reduced INOS fluorescence intensity and enhanced CD206 fluorescence intensity, with the ZSC group showing the lowest fluorescence intensity of INOS and the highest elevation of fluorescence intensity of CD206 among all treatment groups. As shown in Fig. 5 N and S19, ZSC modulated the HO-1/STAT3/NF-κB axis via NF-κB suppression and HO-1/STAT3 upregulation, consequently attenuating classical M1 polarization.

ZSC regulated SCs for promoting neuroregeneration and angiogenesis

SCs play a crucial role in nerve regeneration around wounds. When nerves are damaged, SCs exhibit proliferation, migration, and channel formation toward target neurons, thereby guiding regeneration. Concurrently, SCs synthesize and secrete laminin and neurotrophic factors, markedly enhancing nerve fiber and axonal regeneration. It accelerates skin tissue repair and ameliorates diabetic wound neuropathy. To elucidate ZSC’s regulatory effects on SCs’ physical and bioactive properties, ‌we evaluated morphological changes of SCs using immunofluorescence staining. Compared with the more spherical morphology in untreated HG-SCs group, Phalloidin staining of HG-SCs showed a spreading cytoskeleton and formation of protuberances after treatment with ZSC, revealing the ZSC-mediated promotion of cell adhesion and morphogenesis of HG-SCs (Fig. 6 A). Compared to the untreated HG-SCs, SRC-CDs, ZS, and ZSC enhanced cell viability of HG-SCs, with the ZSC-treated group showing the highest cell viability reaching up to 95% (Figure S20). Meanwhile, the results (Figure S21 and 6B) showed that the migration effects of HG-SCs were significantly promoted after incubation with SRC-CDs, ZS, and ZSC within 24 h, and induced a higher number of migrated cells and faster migration rate as compared to untreated HG-SCs, indicating their effective ability to promote migration of HG-SCs in vitro. Notably, ZSC exhibited a synergistic effect by combining the functions of SRC-CDs and ZS, leading to the fastest migration rate and the highest number of cells penetrating the chamber membrane.

Fig. 6 — (A) Representative immunostaining images of SCs (control group) and HG-SCs treated with SRC-CDs, ZS, and ZSC for 24 h. The scale bar is 50 μm. (B) Migration pictures of HG-SCs treated with SRC-CDs, ZS, and ZSC (n = 3). The scale bar is 100 μm. (C) Cell scratch images in HUVECs (control group) and HG-HUVECs treated with SCM (HG) and SCM (HG + ZSC) at 24 h and 48 h (n = 3). The scale bar is 500 μm. (D) Quantification of cellular migration level in HUVECs (control group) and HG-HUVECs treated with SCM (HG) and SCM (HG + ZSC) at 24 h and 48 h. The data are expressed as the mean ± SD (n = 3), ^*p < 0.05, ^***p < 0.001. (E) In vitro images of tube formation in HUVECs (control group) and HG-HUVECs treated with SCM (HG) and SCM (HG + ZSC) (n = 3). The scale bar is 200 μm. (F) Quantitative analysis of number of tube formation in HUVECs (control group) and HG-HUVECs treated with SCM (HG) and SCM (HG + ZSC). The data are expressed as the mean ± SD (n = 3), ^***p < 0.001. (G, H) Expression levels of BDNF and NGF in SCs (control group) and HG-SCs treated with SRC-CDs, ZS, and ZSC for 24 h. The data are expressed as the mean ± SD (n = 3), ^**p < 0.01, ^***p < 0.001. (I) Western blot images of c-Jun, MBP, and VEGF in SCs (control group) and HG-SCs treated with SRC-CDs, ZS, and ZSC (n = 3).

It has been reported that HG typically downregulates c-Jun and upregulates myelin basic protein (MBP), leading to impaired differentiation and disrupted myelin structure [45]. This finding prompted us to investigate whether ZSC similarly modulated the function of HG-SCs via the same pathway. Western blot (WB) analysis (Fig. 6I and S22) showed that ZSC improved HG-SCs function by upregulating c-Jun and reducing MBP, which are involved in differentiation and myelination. This effect is achieved through antioxidant effects, zinc supplementation, anti-inflammatory actions, and metabolic regulation, ultimately leading to improved myelin formation and nerve function in diabetic conditions. Although MBP as a key structural protein of the myelin sheath could impair subsequent remyelination if suppressed excessively or chronically [46–48], our results showed that moderate downregulation of MBP in the early pathological state of the diabetic wound microenvironment could relieve its inhibition on SCs dedifferentiation and axonal outgrowth, and clear the way for regeneration. Additionally, a key role of SCs is to release various cytokines and nerve growth factors that promote axonal regeneration, thereby promoting the reconstruction of wound innervation. Therefore, we detected NGF and BDNF levels in the supernatant of HG-SCs treated with different administrations. As shown in Fig. 6G and H, compared to the untreated HG-SCs group and other treated groups, BDNF and NGF levels in the culture medium of ZSC-treated HG-SCs were significantly elevated. Therefore, after treatment with SCM (HG) and SCM (HG + ZSC), neurite outgrowth was observed in HG-PC12 cells (Figure S23). These results indicate that, consistent with a previous report, ZSC promoted the secretion of neurotrophic factors from HG-SCs, resulting in neuronal maturation and axonal growth. According to previous reports [49], SCs release VEGF, thus specifically activating the multiplication and movement of endothelial cells. These cells form intimate structural and biochemical linkages with vasculature, generating a crucial neuron-blood vessel system required for tissue regeneration. Therapeutic approaches utilizing SCs or substances that boost their function have demonstrated enhanced vascular formation and comprehensive healing of diabetic wounds [50]. Therefore, we next asked whether ZSC-induced improved function of HG-SCs contributed to the promotion of angiogenesis. Western blot analysis (Fig. 6I and S22) further corroborated that ZSC induced the more secretion of VEGF from HG-SCs. The proliferation and migration of HG-HUVECs were investigated after incubation with SCM (HG) and SCM (HG + ZSC). In Fig. 6 C, D, E and F, compared with untreated HG-HUVECs and SCM (HG) treated HG-HUVECs, angiogenesis was significantly enhanced as evidenced by the highest migration rates and most tube formation in HG-HUVECs treated with SCM (HG + ZSC). All results indicated that HG-SCs were further activated by ZSC and secreted more pro-angiogenic factors like VEGF, thus possibly accelerating the proliferation and migration of HG-HUVECs in vitro. In addition, we further investigated the effects of ZSC-SCHY on angiogenesis and neurogenesis related factors in vivo. As shown in Figure S24, immunofluorescence staining revealed that the fluorescence intensity of VEGF protein in the wound tissue of diabetic rats in the ZSC-SCHY treated group was significantly higher than that in the diabetic model group (DM group), indicating that ZSC-SCHY effectively promotes VEGF protein expression. Furthermore, ELISA quantitative analysis demonstrated that, compared with DM group, the protein levels of NGF and BDNF in diabetic wound tissue were significantly elevated in the ZSC-SCHY treated group. In conclusion, our results confirm that ZSC-SCHY exerts significant pro-angiogenic and pro-neurogenic effects, and its mechanism of action is closely associated with the upregulation of key factors such as VEGF, NGF, and BDNF.

ZSC-SCHY as a theragnostic pH-responsive indicator acted on real-time diagnosis and enhanced diabetic wound repair

To investigate the therapeutic effects of ZSC-SCHY on diabetic chronic wounds, we selected male SD rats weighing 180–220 g and established a type 1 diabetes model through STZ induction, systematically evaluating their ability to real-time visualization diagnosis and promotion of wound healing rate and tissue repair quality (Fig. 7 A). The pH transition in diabetic wound healing reflects the dynamic interplay and the shift from alkaline to acidic conditions is essential for proper wound healing. Diabetic wounds typically start with a weakly alkaline pH (7.4–8.5) due to bacterial colonization and infection, tissue necrosis and cellular debris accumulation. As healing progresses, the microenvironment shifts to weakly acidic pH (6.0–7.0) through enhanced generation of acidic byproducts, fibroblast proliferation, collagen synthesis, and release of protons released by macrophage-mediated phagocytosis [51]. As shown in Fig. 7B, untreated diabetic wounds (DM group) exhibited a gradual pH decline from 8.3 to 8.2 during the initial 4-day period, further reducing to 7.5 by day 7. Conversely, SCHY and ZSC-SCHY therapies prompted an accelerated pH shift from 8.3 to 7.4 within 3 days, progressing to a weakly acidic state (pH = 6.9) by day 7. The data indicated that persistent mild alkalinity in unmanaged diabetic wounds fosters microbial colonization and exacerbates inflammatory responses. Crucially, both hydrogels exhibited pH-modulating properties, facilitating a timely transition to the therapeutically advantageous acidic microenvironments during critical phases of tissue repair. The pH, as a biomarker of healing progression, correlates with healing progression and prognosis. For example, specifically, alkaline pH (7.4–8.5) indicates the early inflammatory phase with potential poor healing, and acidic pH (6.0–7.0) reflects active healing and tissue remodeling process [52]. The pH changes provide immediate feedback on treatment effectiveness. Therapeutic interventions can be adjusted based on pH variation. Due to the significant changes in fluorescence intensity of SRC-CDs under different pH values, it was supposed that ZSC-SCHY could exhibit different fluorescence intensity at wound site with different pH and could act as a non-invasive, real-time pH monitoring tool for evaluating and predicting wound recovery levels in diabetic patients. Therefore, we further evaluated the pH monitoring ability of ZSC-SCHY in diabetic wounds. As shown in Fig. 7C, ZSC-SCHY was used to measure wound pH at different time periods. ZSC-SCHY was applied to the wound of diabetes to make it color. The hydrogel was photographed with a smartphone, and the RGB values were extracted. By substituting the extracted RGB values into the fitting curve and converting them into the corresponding pH values, the pH changes of diabetic wound microenvironment were evaluated. The results showed that the pH value derived from the RGB values collected at ZSC-SCHY treated diabetic wound site demonstrated good agreement with the pH values measured by the pH test paper, confirming the reliability and feasibility of ZSC-SCHY in real-time pH monitoring. The antimicrobial performance of ZSC-SCHY was also assessed through bacterial culture assays using isolates from the treated diabetic wounds. As illustrated in Fig. 7G and I, the untreated diabetic wound (DM group) exhibited significantly greater levels of microbial proliferation than the sham group, attributable to the hyperglycemic conditions. Both SCHY and ZSC-SCHY displayed superior bactericidal activity at wound sites relative to DM group, as quantified by sustained growth inhibition. Giemsa staining (Fig.7J) further revealed that compared to the sham group, the untreated diabetic wound showed obvious bacterial presence. After intervention with ZSC-SCHY, bacterial infiltration was essentially eliminated, which confirms that it can effectively clear bacterial infections in diabetic wounds. The antibacterial performance of ZSC‑SCHY arises from its multimechanistic synergy. First, the amide bonds in the ZSC‑SCHY structure can be cleaved in a stimulus‑responsive manner, dynamically modulating the wound pH microenvironment. This process actively shifts the typically alkaline infected microenvironment of diabetic wounds toward a weakly acidic state, directly inhibiting bacterial colonization and proliferation [53]. Second, ZSC‑SCHY can sustainably release Zn²⁺, which exert potent antimicrobial effects through multiple pathways, including disruption of bacterial cell membranes, induction of ROS accumulation, and inhibition of key enzymatic activities. Furthermore, the three‑dimensional network of the hydrogel enhances bacterial adsorption and disruption via physical contact. Additionally, the good hemostatic performance of ZSC-SCHY was demonstrated in vivo rats tail hemostasis assay (Fig. 7D). It was used to evaluate the hydrogel’s hemostatic capabilities by quantitatively determining the degree of bleeding at the tail bleeding site after applying the hydrogel. Compared with the untreated group (Sham group), the ZSC-SCHY group showed significant hemostatic ability, with a significant reduction in blood loss. This result may be due to the excellent water absorption performance and self-healing function conferred by the 3D porous structure of the ZSC-SCHY. Given their direct cellular interaction, the biocompatibility of hydrogel dressings is critically important.‌ Hemolysis tests confirmed the biocompatibility of all administrations showing less than 1% hemolysis ‌(Figure S25). Furthermore, to comprehensively assess the potential systemic toxicity, H&E staining was performed on sections of the heart, liver, spleen, lung, and kidney from diabetic rats treated with daily covering administration of SCHY and ZSC-SCHY for 14 days. The results ‌(Figure S26) showed that compared with the sham group, no significant pathological damage was observed in both SCHY and ZSC-SCHY treated groups, indicating that at the given dosage and treatment duration, SCHY and ZSC-SCHY did not induce organ toxicity, indicating their good biocompatibility. Additionally, the body weight of diabetic rats remained stable throughout the treatment period ‌(Figure S27), providing further evidence of the high biocompatibility and safety profile of SCHY and ZSC-SCHY.

Subsequent investigations evaluated the therapeutic influence of SCHY and ZSC-SCHY on diabetic wound repair dynamics. Results (Fig. 7E, F, H) showed markedly impaired re-epithelialization and prolonged wound recovery as evidenced by the larger wound area and lower wound healing rate in diabetic wound (DM group) as compared to normal wound (sham group), confirming hyperglycemia-induced healing retardation. Both SCHY and ZSC-SCHY accelerated diabetic wound healing process during the 14-day observation period. Among these, the ZSC-SCHY group showed the most significant therapeutic effects, characterized by the smallest wound area, highest wound healing rate, and optimal re-epithelialization levels. In the early stage of diabetic wounds (day 3), as shown in Fig. 7 J, it showed that the DM group exhibited increased inflammatory cell infiltration, diminished granulation tissue formation, and reduced fibroblast counts. In contrast, ZSC-SCHY treatment markedly decreased inflammatory cells while promoting granulation tissue and vascular development at the wound site.‌ By postoperative day 7, ZSC-SCHY-treated wounds displayed heightened neovascular density relative to other interventions. Immunohistochemistry staining confirmed significantly elevated formation of nascent vasculature and highest CD31 expression (an established endothelial proliferation biomarker) in ZSC-SCHY treated group as compared to DM group and other treated groups. The observed beneficial effects may be due to the dual role of ZSC in promoting angiogenesis and reducing oxidative stress. H&E sections on day 14 showed that collagen fibers were densely packed and organized in a regular pattern in ZSC-SCHY treated group, indicating the initiation of the remodeling phase.‌ Compared to the SCHY treated group, there was higher collagen content and density in ZSC-SCHY treated group, attributed to the role of ZSC in promoting collagen regeneration and facilitating the transition of wound healing from the proliferative phase to the remodeling phase. Meanwhile, the final stage of wound healing involves extracellular matrix remodeling, specifically with the synthesis and rearrangement of collagen fibers. Masson staining on day 14 confirmed that the highest density and most organized structure of the newly formed collagen fibers were observed in ZSC-SCHY treated group, indicating that this treatment effectively promoted collagen regeneration and enhanced post-healing skin recovery quality.

ZSC-SCHY regulated the M1/M2 polarization of macrophages and promoted nerve regeneration in vivo

It was reported that diabetic wounds exhibit significantly prolonged inflammatory responses due to long-term hyperglycemic metabolic disorders and oxidative stress, leading to imbalanced-excessive activation of pro-inflammatory M1 macrophages [54, 55]. In diabetic wounds, persistent activation of M1 macrophages results in excessive accumulation of pro-inflammatory factors, while polarization of M2 macrophages is blocked. These factors collectively maintain the wound microenvironment in a chronic inflammatory state, thereby hindering the proliferation and remodeling phases of tissue repair [56].

Considering the prolonged oxidative stress-associated inflammatory response in the diabetic wound healing process, we investigated ZSC-SCHY’s capacity to facilitate M1-to-M2 phenotypic transition and subsequently explored its anti-inflammatory effects through cytokine modulation. We first performed DHE staining and analyzed the change of ROS level in wound tissue receiving different treatments. As shown in Fig. 8 A and B, compared to the sham group, the DM group exhibited significantly increased DHE fluorescence signal intensity, indicating elevated ROS accumulation levels in diabetic wound tissue. After treatment with SCHY and ZSC-SCHY, the DHE fluorescence intensity in wound tissue was reduced. Notably, ZSC-SCHY showed the lowest DHE fluorescence intensity, demonstrating effective ROS scavenging. Furthermore, immunofluorescence analysis of M1/M2 macrophage markers (INOS/CD206) in treated tissue sections (Fig. 8 C, D, E and F) revealed that ZSC-SCHY facilitated macrophage reprogramming from M1 (downregulation of INOS) to M2 (upregulation of CD206), suppressing pro-inflammatory responses at the wound site.‌ Additionally, pro-inflammatory factor secretion of TNF-α was markedly decreased while anti-inflammatory factors of IL-10 were significantly increased (Fig. 8G, H, I and J). All results demonstrated the anti-inflammatory efficacy of ZSC-SCHY on diabetic wounds by modulating macrophage polarization and reducing inflammatory factor expression.

Fig. 8 — (A) Fluorescence images of DHE in diabetic wound subjected to the daily covering treatment of SCHY and ZSC-SCHY on 7th day (n = 3). The scale bar is 100 μm. (B) Relative fluorescence intensity of DHE in diabetic wound subjected to the daily covering treatment of SCHY and ZSC-SCHY on 7th day. The data are expressed as the mean ± SD (n = 3), ^***p < 0.001. (C, E, G, I) Immunofluorescence images of INOS, CD206, TNF-α, and IL-10 in diabetic wounds subjected to the daily covering treatment of SCHY and ZSC-SCHY on day 3 (n = 3). The scale bar is 100 μm. (D, F, H, J) Quantitative analysis of relative immunofluorescence intensity of INOS, CD206, TNF-α, and IL-10 in diabetic wound subjected to the daily covering treatment of SCHY and ZSC-SCHY on day 3. The data are expressed as the mean ± SD (n = 3), ^*p < 0.05, ^**p < 0.01, ^***p < 0.001. (K) Immunofluorescence images of GAP-43 in diabetic wounds subjected to the daily covering treatment of SCHY and ZSC-SCHY on 14th day (n = 3). The scale bar is 100 μm. (L) Quantitative analysis of relative immunofluorescence intensity of GAP-43 in diabetic wound subjected to the daily covering treatment of SCHY and ZSC-SCHY on day 14. The data are expressed as the mean ± SD (n = 3), ^**p < 0.01, ^***p < 0.001. (M) Immunofluorescence images of S100B in diabetic wounds subjected to the daily covering treatment of SCHY and ZSC-SCHY on 14th day (n = 3). The scale bar is 100 μm. (N) Quantitative analysis of relative immunofluorescence intensity of S100B in diabetic wound subjected to the daily covering treatment of SCHY and ZSC-SCHY on day 14. The data are expressed as the mean ± SD (n = 3), ^**p < 0.01, ^***p < 0.001

Furthermore, ZSC-SCHY mediated nerve regeneration in diabetic wounds was accessed by checking cutaneous nerve axons and myelin with GAP-43 and S100B, respectively. As shown in Fig. 8 K and L, skin tissue from ZSC-SCHY treated group exhibited the higher expression of GAP-43 as compared to the other treated groups, suggesting that ZSC-SCHY induced cutaneous nerve fiber regrowth as evidenced by the upregulation of GAP-43 as a membrane-associated axonal regeneration marker at the wound site. These sensory nerves transmit peripheral signals and are critical for skin tissue homeostasis. Furthermore, ZSC-SCHY induced the proliferation of SCs as evidenced by higher expression of S100B in the diabetic wound as compared to other treated groups (Fig. 8M and N). It indicated that ZSC-SCHY contributed to tissue regeneration through tubular formation, axonal guidance, and neurotrophic factor secretion.

Discussion

Traditional methods of diabetic wound treatment include wound debridement to remove necrotic tissue, application of antimicrobial dressings to prevent infection [57], compression therapy to improve blood flow [58], and offloading techniques to reduce pressure on the wound site [59]. These conventional approaches often rely on frequent clinical visits for wound assessment and dressing changes, which can be inconvenient for patients and may lead to delayed detection of complications such as infection or delayed healing. The real-time monitoring in conventional approaches was absent, potentially enabling wound deterioration prior to intervention. Furthermore, traditional therapies frequently overlook the underlying pathophysiological mechanisms of diabetic wounds, including impaired angiogenesis, peripheral neuropathy, and persistent inflammation, thereby limiting their overall efficacy.

The integration of diabetic wound diagnosis and treatment represents a significant advancement in wound care management, as it enables real-time monitoring of wound healing progression while simultaneously delivering therapeutic interventions. This integrated approach provided continuous assessment of the wound microenvironment including pH changes, infection status, and healing progression, allowing for timely adjustments in treatment strategies. The theranostic approach reduces the need for frequent clinical visits and invasive procedures, improving patient compliance and reducing healthcare costs while ensuring optimal treatment outcomes. By combining diagnostic capabilities with therapeutic delivery, this integrated system can detect early signs of complications, such as infection or delayed healing, and respond immediately with appropriate therapeutic interventions, preventing the progression to more severe conditions. The real-time feedback provided by integrated systems enables personalized treatment regimens that can be tailored to individual patient needs and wound characteristics, leading to more effective and efficient wound healing.

We developed an innovative pH responsive fluorescent dressing ZSC-SCHY for rapid monitoring and effective treatment of diabetic wounds. SRC-CDs we obtained offer distinct advantages over those from natural carbon-based substances. Their natural multicomponent composition enables in situ self-doping with N/O heteroatoms, eliminating the need for post-synthetic modification. More importantly, they inherently inherit the herb’s synergistic bioactivities such as anti-inflammation and antioxidation, creating a theranostic nanomaterial that integrates fluorescence with therapeutic function. In contrast, CDs from simple precursors lack intrinsic pharmacology and are limited to single compound activity. This makes SRC-CDs uniquely suited for applications requiring both sensing and multifunctional therapy like diabetic wound management. The pH-sensitive SRC-CDs enable the hydrogel to respond to different pH microenvironments by displaying fluorescence intensity and color changes, allowing real-time monitoring of wound pH. Furthermore, H₂S generated by ZSC-SCHY exhibits dual efficacy-acting both as an active molecule directly involved in treatment and as a “nano-motor” to deliver drugs into the deeper wound, further improving treatment efficacy. In virtue of the combination of SRC-CDs, Zn²⁺, and H₂S, ZSC-SCHY effectively alleviates wound oxidative stress damage, accelerates angiogenesis to improve local blood supply, and simultaneously promotes SCs-mediated cutaneous nerve regeneration and functional recovery, thereby comprehensively accelerating the wound healing process. More importantly, its pH visual monitoring function greatly simplifies wound infection diagnosis, enabling intuitive judgment of wound status without complex testing. In conclusion, ZSC-SCHY successfully established a visual monitoring-intelligent response therapy, realizing an integrated diagnostic and therapeutic approach.

Although ZSC-SCHY contributed to precise treatment of diabetic wounds, related work remains in the preliminary exploration stage with several limitations requiring future research to overcome. It lacks comprehensive evaluation of the hydrogel’s long-term biocompatibility and potential immunogenicity in vivo, which is crucial for clinical translation. The hydrogel’s performance in different types and severities of diabetic wounds was not explored, limiting its generalizability. There is insufficient evaluation of the potential side effects or toxicity associated with the sustained release of Zn²⁺ and H₂S. Particularly, long‑term systemic Zn²⁺ accumulation risk in diabetic rats remains unassessed. The pH‑triggered, sustained release of Zn²⁺ from ZS, combined with potential diabetic nephropathy impairing renal clearance, may lead to systemic zinc overload. Current 14‑day studies lack pharmacokinetic data on serum/organ Zn²⁺ levels and extended organ histopathology. Future work will be conducted to perform comprehensive biocompatibility studies, including long-term safety evaluation, immunogenicity assessment, and toxicity studies to ensure clinical safety. The hydrogel composition will be optimized for enhanced mechanical strength, controlled release kinetics, and improved stability under various physiological conditions. The therapeutic efficacy in different diabetic wound models with varying severities and comorbidities will be evaluated to assess the hydrogel’s broad applicability. Finally, the potential synergistic effects with other wound healing therapies, such as growth factors, stem cells, or conventional wound care approaches, will be explored to enhance overall treatment outcomes.

Conclusion

We engineered a novel fluorescent hydrogel (ZSC-SCHY) dressing for diabetic wound management, combining real-time pH monitoring with multimodal therapy. ZSC-SCHY utilizes pH-responsive SRC-CDs that exhibit wound microenvironmental pH-dependent fluorescence shifts, enabling visual wound assessment. ZSC-SCHY enhanced treatment effectiveness via inflammation modulation, vascular reconstruction, and neuroregeneration. Specifically targeting alkaline diabetic wounds, ZSC-SCHY achieves dual functionality - acidifying the diabetic wound bed while acting as H₂S gas nanomotors to enhance drug penetration. Owing to the synergistic effect of SRC-CDs, Zn²⁺ and H₂S, ZSC-SCHY demonstrates comprehensive efficacy by reducing oxidative stress, inducing macrophage M2 polarization, promoting angiogenesis, and activating SCs. ZSC-SCHY holds a promising potential for representing an advanced theranostic platform for diabetic wound care.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Material 1^{(37.8MB, docx)}

Acknowledgements

This work was supported by the grants from Natural Science Foundation of Liaoning Province (2023-MS-306). We thank the support of the above fund. We thank Tao Xu, Jia Liang, Hongdan Li, Jing Hu, Yan Zhao and Song Zhao from the Life Science Institute of Jinzhou Medical University for their technical support.

Author contributions

Y. S., X. S., X. G. and M. S. conceived the study, designed the experiments, and wrote the manuscript. G. Z., M. S., F. L., R. L. and Y. Z. assisted in some of the cell and animal experiments. L. Z. and Y. S. provided experimental design and professional guidance, as well as the research platform and funding. All authors have approved the final version of the manuscript.

Funding

This work was supported by the grants from Natural Science Foundation of Liaoning Province (2023-MS-306). We thank the support of the above fund.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

All experiments were compliant with the ethical standards of the Animal Ethical Committee and responsible authorities of Jinzhou Medical University (animal ethics committee approval number: 240173-5). It followed all guidelines, regulations, legal, and ethical standards as required for animals and was approved under the National Guidelines for Animal Protection.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yan Sun, Xiangchen Su, Xinrong Geng and Mengdi Sun contributed equally to this work.

Contributor Information

Yijie Shi, Email: shiyijie119@163.com.

Liang Zhao, Email: liangzhao79@163.com.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material 1^{(37.8MB, docx)}

Data Availability Statement

No datasets were generated or analysed during the current study.

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[CR27] 27.Liu HC, Huang CH, Chiang MR, Hsu RS, Chou TC, Lu TT, Lee IC, Liao LD, Chiou SH, Lin ZH, Hu SH. Sustained Release of Nitric Oxide-Mediated Angiogenesis and Nerve Repair by Mussel-Inspired Adaptable Microreservoirs for Brain Traumatic Injury Therapy. Adv Healthc Mater. 2024;13(25):e2302315. [DOI] [PubMed] [Google Scholar]

[CR28] 28.Chan YC, Lin YH, Liu HC, Hsu RS, Chiang MR, Wang LW, Chou TC, Lu TT, Lee IC, Chu LA, Hu SH. In situ magnetoelectric generation of nitric oxide and electric stimulus for nerve therapy by wireless chargeable molybdenum carbide octahedrons. Nano Today. 2023;51000:14. [Google Scholar]

[CR29] 29.Li G, Zhang R, Chen K, Dong J, Yang Z, Chen H, Wang H, Wang H, Lei H, Bao W, Zhang M, Xiao Z, Cheng L, Dong Z. Zinc sulfide nanoparticles serve as gas slow-release bioreactors for H₂S therapy of ischemic stroke. Biomaterials. 2025;315:122912. [DOI] [PubMed] [Google Scholar]

[CR30] 30.Dong X, Zhang H, Duan P, Liu K, Yu Y, Wei W, Wang W, Liu Y, Cheng Q, Liang X, Huo Y, Yan L, Yu A, Dai H. An injectable and adaptable hydrogen sulfide delivery system for modulating neuroregenerative microenvironment. Sci Adv. 2023;9(51):eadi1078. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[CR33] 33.Geng X, Li W, Qu J, Wang Q, Che T, Yan L, Cui H, Liu D, Qin S. Modified Fish-Skin-Collagen-Based Hydrogels with Antioxidant and Antibacterial Functions for Diabetic Wound Healing. Adv Healthc Mater. 2025;14(21):e2501456. [DOI] [PubMed] [Google Scholar]

[CR34] 34.Kang H, Kim S, Lee JY, Kim B. Inhibitory effects of ginsenoside compound K on lipopolysaccharide-stimulated inflammatory responses in macrophages by regulating sirtuin 1 and histone deacetylase 4. Nutrients. 2023;15(7):1626. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[CR36] 36.Zhou Z, Zhang D, Ning X, Jin L, Lin Y, Liang C, Wen X, Huang T, Zhou J, Zhang Y. An antibacterial, antioxidant and hemostatic hydrogel accelerates infectious wound healing. J Nanobiotechnol. 2025;23(1):49. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR37] 37.Wang W, Yao H, Xia J, Wan X, Wu J. Chitosan-Based immunomodulatory bioadhesive hydrogel promotes liver hemostasis and repair. Carbohydr Polym. 2025;353:123268. [DOI] [PubMed] [Google Scholar]

[CR38] 38.Ji X, Zhou J, Zhou Z, Liu Z, Yan L, Li Y, Guo H, Su W, Wang H, Ni D. Recovering skin-nerve interaction by nanoscale metal-organic framework for diabetic ulcers healing. Bioactive Mater. 2024;42:112–23. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR39] 39.Tan X, Lin N, Yang S, Gong H, Wang M, Li N, Liu F, Rao D, Wu Y, Tang J, Yang Q. AuCu@CuO₂ aerogels with H₂O₂/O₂ self-supplying and quadruple enzyme-like activity for MRSA-infected diabetic wound management. Adv Sci. 2025;12(27):e2502391. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR40] 40.Yuan Z, Zhang W, Wang C, Zhang C, Hu C, Liu L, Xiang L, Yao S, Shi R, Fan D, Ren B, Luo G, Deng J. A microenvironment-adaptive GelMA-ODex@RRHD hydrogel for responsive release of H₂S in promoted chronic diabetic wound repair. Regenerative biomaterials. 2024;12:rbae134. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR41] 41.Wu F, Pang Y, Liu J. Swelling-strengthening hydrogels by embedding with deformable nanobarriers. Nat Commun. 2020;11(1):4502. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR42] 42.Guo Y, Yang L, Yao L, Zhou C, Zhu Y, Xu C, Wang W, Song J, Zhang M, Deng Z. Carbon dots derived from Ligusticum Chuanxiong mitigate cardiac injury by disrupting the harmful oxidative stress-apoptosis cycle. J Nanobiotechnol. 2025;23(1):391. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR43] 43.Chen Y, Cai J, Liu D, Liu S, Lei D, Zheng L, Wei Q, Gao M. Zinc-based metal organic framework with antibacterial and anti-inflammatory properties for promoting wound healing. Regenerative biomaterials. 2022;9:rbac019. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR44] 44.Yang H, Tan M, Gao Z, Wang S, Lyu L, Ding H. Role of hydrogen sulfide and hypoxia in hepatic angiogenesis of portal hypertension. J Clin Transl Hepatol. 2023;11(3):675–81. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR45] 45.Han S, Gao L, Dou X, Wang Z, Yang K, Li D, Yuan Y, Xing C, Jiang B, Tian Y, Feng CL, Zhang P. Chiral hydrogel nerve conduit boosts peripheral nerve regeneration via regulation of schwann cell reprogramming. ACS Nano. 2024;18(41):28358–70. [DOI] [PubMed] [Google Scholar]

[CR46] 46.Wang H, Zhang M, Liu M, Liu J, Gong J, Yin L, Yang Y, Zhao Y. Chitooligosaccharides accelarate myelin clearance by Wipi1 mediated Schwann cell autophagy promoting peripheral nerve regeneration. Regenerative biomaterials. 2025;12:rbaf044. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR47] 47.Gitik M, Elberg G, Reichert F, Tal M, Rotshenker S. Deletion of CD47 from Schwann cells and macrophages hastens myelin disruption/dismantling and scavenging in Schwann cells and augments myelin debris phagocytosis in macrophages. J Neuroinflamm. 2023;20(1):243. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR48] 48.Moretti M, Caraffi R, Lorenzini L, Ottonelli I, Sannia M, Alastra G, Baldassarro VA, Giuliani A, Duskey JT, Cescatti M, Ruozi B, Aloe L, Vandelli MA, Giardino L, Tosi G, Calzà L. Combo Multi-Target Pharmacological Therapy and New Formulations to Reduce Inflammation and Improve Endogenous Remyelination in Traumatic Spinal Cord Injury. Cells. 2023;12(9):1331. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR49] 49.Jin F, Li T, Wei Z, Xiong R, Qian L, Ma J, Yuan T, Wu Q, Lai C, Ma X, Wang F, Zhao Y, Sun F, Wang T, Feng ZQ. Biofeedback electrostimulation for bionic and long-lasting neural modulation. Nat Commun. 2022;13(1):5302. [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

A pH-inspired hydrogel enables real-time monitoring and precise treatment of diabetic wounds

Yan Sun

Xiangchen Su

Xinrong Geng

Mengdi Sun

Ge Zhang

Mingzhu Song

Fang Li

Ruizhen Lv

Yuting Zhao

Yijie Shi

Liang Zhao

Abstract

Graphical abstract

Supplementary Information

Introduction

Fig. 1.

Materials and methods

Materials

Cell culture

Preparation and characterization of SRC-CDs, ZS, and ZSC

Synthesis and characterization of SCHY and ZSC-SCHY

Analysis of the motion behavior of ZS in vitro and in vivo

In vitro evaluation of pH visual monitoring

In vitro cytocompatibility evaluation

Evaluation of cellular proliferation, migration, and in vitro angiogenesis assay‌

Assay on secretion of neurotrophic factors and axon outgrowth of PC12 cells

Establishment of type 1 diabetic rat skin wounds and theranostic intervention

IHC staining assay

Immunofluorescence staining

Western blot analysis

Statistical analysis

Results

Characterization of SRC-CDs, ZS, and ZSC

Fig. 2.

The pH-responsive fluorescence characteristics of SRC-CDs

Fig. 3.

The physical characterization and adhesive properties of ZSC-SCHY

Fig. 4.

ZSC induced angiogenesis and M1/M2 transition of macrophage

Fig. 5.

ZSC regulated SCs for promoting neuroregeneration and angiogenesis

Fig. 6.

ZSC-SCHY as a theragnostic pH-responsive indicator acted on real-time diagnosis and enhanced diabetic wound repair

Fig. 7.

ZSC-SCHY regulated the M1/M2 polarization of macrophages and promoted nerve regeneration in vivo

Fig. 8.

Discussion

Conclusion

Electronic Supplementary Material

Acknowledgements

Author contributions

Funding

Data availability

Declarations

Ethics approval and consent to participate

Competing interests

Footnotes

Contributor Information

References

Associated Data

Supplementary Materials

Data Availability Statement

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