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Zinc–gallic acid–polylysine nanocomplexes with enhanced bactericidal activity for the treatment of bacterial keratitis

  • Kaijun Li EMAIL logo , Ya Zhang , Kaihui Cheng , Chengcheng Wu , Qiao Jin and Ling Yu EMAIL logo
Published/Copyright: March 10, 2025
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e-Polymers
From the journal e-Polymers Volume 25 Issue 1

Abstract

Bacterial keratitis is a common infectious eye disease. Conventional antibiotic eye drops are becoming less effective due to antibiotic resistance. Herein, we design an innovative transition metal ion-based nano-delivery system for the treatment of bacterial keratitis. Zinc (Zn2+)–gallic acid–poly-l-lysine nanocomplex (ZGNC) is designed by coordination interaction. ZGNC is stable in a physiological environment and can be dissociated in an acidic infected microenvironment. The positively charged ZGNC can be effectively adhered onto bacterial cells and subsequently realizes in situ release of Zn2+, leading to much better bactericidal effect than free Zn2+. Importantly, ZGNC maintains excellent bactericidal activity in a protein-rich environment, while free Zn2+ is completely invalid to eradicate bacteria in a protein-rich environment. The in vivo bactericidal ability of ZGNC is further confirmed in a murine bacterial keratitis model. This research provides a promising method to treat bacterial keratitis by a transition metal ion-based nano-delivery system.

Graphical abstract

Keywords: antibacterial; metal ion delivery system; metal-phenolic network; coordination interaction; bacterial keratitis

1 Introduction

Bacterial keratitis is a common but potentially sight-threatening ocular infection (1,2). If not treated timely and properly, bacterial keratitis can rapidly deteriorate, leading to visual impairment and even blindness (3). In the clinic, the first-line treatment of bacterial keratitis is the topical instillation of antibiotic eye drops such as levofloxacin. However, antibiotic resistance is becoming a more and more serious global issue that significantly restricts the therapeutic efficacy of conventional antibiotics, which even leads to the failure of antibiotic therapy (4,5). It is urgently needed to develop alternative antibacterial strategies to fight against drug-resistant bacteria (6,7,8,9,10). On the other hand, although eye drops are the most accessible therapy for ophthalmic diseases, the therapeutic efficiency of eye drops is relatively low because of the very short ocular retention time caused by rapid tear turnover (11,12). Therefore, to improve the therapeutic efficiency of eye drops, it is crucial to improve drug bioavailability by prolonging ocular retention time. The fabrication of nano eye drops might be an effective way to prolong ocular retention time by endowing nanoparticles with targeting and adhering ability (13,14,15).

Transition metal ions (Ag+, Cu2+, Zn2+, etc.) were used as antimicrobials and disinfectants thousands of years ago. Transition metal ions can kill bacterial cells by multiple bactericidal mechanisms, such as protein dysfunction, destruction of cell membrane, and damage of nucleic acid (16,17,18,19). However, free transition metal ions are unstable and can be easily inactivated by surrounding proteins and cells, which makes it invalid to use metal ions to treat internal bacterial infections. To address this issue, metal or metal oxide nanoparticles are usually prepared for antibacterial applications, such as silver nanoparticles and zinc oxide nanoparticles (20,21,22). However, it is very difficult to release metal ions from these metallic nanoparticles due to the very stable crystal structure, leading to limited bactericidal efficiency. Meanwhile, the metabolization of the stable metallic nanoparticles in vivo is another critical issue, which will result in abundant deposition of metallic nanoparticles and serious adverse effects (23). Therefore, metallic nanoparticles are not able to be used to treat bacterial infections in vivo. The realization of exogenous metal ions for in vivo sterilization might be a major breakthrough in non-antibiotic therapy. To realize this goal, it is urgently needed to develop innovative delivery systems for metal ions, which can not only protect metal ions from inactivation by proteins but also release metal ions effectively (24,25).

Polyphenols, a class of plant-derived compounds characterized by the presence of multiple phenolic hydroxyl groups, can form pH-sensitive dynamic coordination structures with transition metal ions (26,27,28,29). Their low physiological toxicity and potential anti-inflammatory activities can synergistically enhance the clearance of infections and tissue repair in conjunction with transition metal ions. Therefore, metal ions and polyphenols can form pH-sensitive metal-phenolic networks (MPN), which provides a promising avenue to achieve efficient delivery of metal ions (30,31). Nanocomplexes formed based on metal-polyphenol interaction held great promise for the treatment of bacterial infections (32,33,34).

Herein, a zinc–gallic acid–polylysine nanocomplex (ZGNC) was designed as an innovative nanocarrier of Zn2+ for the treatment of bacterial keratitis. ZGNC was prepared by the self-assembly of Zn2+, gallic acid (GA), and poly-l-lysine (PLL) (Figure 1). By adjusting the composition of ZGNC, ZGNC was expected to adhere to negatively charged bacterial cells by electrostatic interaction. Owing to the pH-sensitive metal-phenolic bonding, ZGNC was stable in the physiological environment, while the rapid release of Zn2+ could be achieved in an acidic infected microenvironment. Meanwhile, the formation of ZGNC could effectively prevent Zn2+ from adsorption by proteins, exhibiting excellent bactericidal ability in a protein-rich environment. The effective adhesion to bacterial cells and rapid Zn2+ release endowed ZGNC with excellent antibacterial activity against both Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative Escherichia coli. The in vivo bactericidal ability of ZGNC was further evaluated on a murine MRSA-induced keratitis model. This innovative strategy for the delivery of transition metal ions may open up a new way to realize bactericidal applications of metal ions in vivo.

Figure 1 Schematic illustration of the preparation and functions of ZGNC.
Figure 1

Schematic illustration of the preparation and functions of ZGNC.

2 Experimental

2.1 Materials

Zn2+ standard solution (1,000 μg·mL−1), GA, and PLL were purchased from Macklin Biochemical Co., Ltd. (Shanghai, China). Bovine serum albumin (BSA), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), 2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride (DAPI), and 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) were obtained from Sigma-Aldrich. Tryptic Soy Broth and Luria-Bertani (LB) agar were procured from Baisi Biotechnology Co., Ltd. (Hangzhou, China). All other reagents and solvents were of analytical grade and used as received without further purification.

2.2 Bacterial strains

The bacterial strains utilized in this research were sourced from the American Type Culture Collection (ATCC). MRSA (ATCC 43300) was chosen as the representative Gram-positive bacterium, while E. coli (ATCC 25922) was selected as the representative Gram-negative bacterium.

2.3 Characterizations

The surface charge and hydrodynamic diameter of ZGNC were detected using dynamic light scattering (DLS) equipment, specifically the Zetasizer Nano-ZS from Malvern Instruments. A transmission electron microscope (TEM) (JEM-1400) was used to observe the morphology of ZGNC. High-angle annular dark field (HAADF) imaging and X-ray energy-dispersive spectroscopy (EDS) were conducted using a high-resolution TEM (JEM 2100F). The morphology of bacteria was characterized using a field emission scanning electron microscope (SEM) (JSM-IT800). X-ray photoelectron spectroscopy (XPS) analysis was performed with an X-ray photoelectron spectrometer (Escalab 250Xi, Thermo). X-ray diffraction (XRD) patterns were obtained using an X-ray diffractometer (Ultima IV). Quantitative analysis of Zn2+ and K+ was carried out using an inductively coupled plasma mass spectrometer (ICP-MS; iCAP RQPlus, Thermo). Optical density values were measured using a Microplate Reader (Multiskan FC, Thermo). Fluorescent images were obtained using a fluorescence microscope (Olympus IX73).

2.4 Preparation of ZGNC

In a typical experiment to prepare ZGNC, 25 mL of ethanol was added to a 200 mL beaker. 200 μL of Zn2+ standard solution, 800 μL of NH3·H2O-HCl buffer solution, and 1.5 mL of H2O were then added. After that, 50 μL of PLL solution (20 mg·mL−1 in water) and 75 μL of GA solution (200 mg·mL−1 in DMSO) were added into the beaker very slowly under magnetic stirring. 25 mg NH4Cl and 20 mg NaOH were put on the paper. A permeable paper was masked on the top of the beaker. The beaker was wrapped in aluminum foil and then put in an oven at 50°C. The self-assembly reaction occurred along with the ammonia (produced by the reaction of NH4Cl and NaOH) permeating the paper and dissolved in the solution. Two hours later, the solution was centrifugated for 5 min and the precipitate was collected, which was washed with ethanol two times. The precipitate was re-dispersed in water to obtain ZGNC dispersion.

2.5 pH-responsive release of Zn2+ from ZGNC

To explore the pH-responsive release of Zn2+ from ZGNC, 1 mL of ZGNC (1 mg·L−1) was placed into a dialysis bag (with a cutoff of 1 kDa) and dialyzed against 9 mL of phosphate-buffered saline (PBS) at pH 7.4 or 6.5. At different time points (5, 15, 30, 45, 60, 120, 180, 240, 300, and 360 min), 20 μL of the dialysate solution was sampled and analyzed using ICP-MS to quantify the concentration of Zn2+. The morphology of ZGNC after incubating at pH 6.5 was characterized using TEM.

2.6 Bacterial counting assay

The gradient dilution method was used to enumerate viable bacteria in either solution or tissue (where tissue was homogenized in 10 mL PBS to obtain a bacterial suspension). In brief, a series of 10-fold dilutions of the bacterial suspension were prepared. Subsequently, 10 μL from each diluted solution was plated onto LB agar plates, and this process was repeated three times. After incubating for 16 h, the number of bacterial colonies in each drop was counted as p. The bacterial count in the original suspension was calculated as p × 10 n+2 (colony-forming unit [CFU]·mL−1), where n represents the corresponding dilution times.

2.7 In vitro bactericidal tests

To assess the in vitro bactericidal efficacy of ZGNC under varied pH/protein conditions, 100 μL of MRSA suspension (∼108 CFU·mL−1 in PBS) were incubated with 50 μL of PBS adjusted to pH 7.4 or pH 6.5, or with a 5 mg·L−1 BSA solution to create different pH/protein environments. Subsequently, 50 μL of H2O, Zn2+ (20 μg·L−1), or ZGNC (5, 10, 15 μg·L−1 Zn2+ equivalent) was added and incubated for 6 h. The remaining bacteria were quantified using a standard bacterial counting assay. After treatment, the solutions were collected and centrifuged to remove bacteria. The K+ concentration in the supernatant was determined using ICP-MS.

2.8 Interaction between ZGNC and MRSA

Fluorescein isothiocyanate-labeled ZGNC (FITC-ZGNC) was prepared by mixing 1 mL of ZGNC (200 μg·L−1) with 10 μL of FITC solution (1 mg·L−1 in DMSO) for 10 min. The mixture was then centrifuged at 10,000 rpm for 4 min to obtain FITC-ZGNC, which was re-dispersed in 1 mL of H2O. To investigate the interaction between ZGNC and MRSA, 50 μL of FITC-ZGNC dispersion was incubated with 200 μL of MRSA suspension (∼108 CFU·mL−1) for 10 min. The mixture was subsequently centrifuged and the collected sediment was stained with a DAPI solution for 20 min, followed by removal of excess DAPI through centrifugation. Finally, the bacteria were re-dispersed in water and the fluorescence microscopy was used to investigate the interaction between ZGNC and MRSA.

2.9 Morphology change of MRSA after treatment

The morphological changes of MRSA following various treatments were examined by SEM. Initially, 200 μL of MRSA (∼108 CFU·mL−1) was separately incubated with 20 μL of H2O, Zn2+, PLL, or ZGNC for 6 h. Subsequently, 10 μL of the bacterial suspension from each treatment was deposited onto a clean silicon pellet. After allowing the liquid to evaporate for 1 h, the drop was removed, and 30 μL of 2.5% glutaraldehyde solution was added for fixation. After another 1 h of fixation, the samples were washed with PBS and dehydrated through a series of ethanol solutions (20%, 40%, 60%, 80%, and 100%). Finally, the samples were air-dried at room temperature and prepared for SEM observation.

2.10 In vitro cytotoxicity study

MTT assay was adopted to evaluate the in vitro cytotoxicity of Zn2+ and ZGNC. Human corneal epithelial cells (HCECs) were bought from the American Tissue Culture Collection (Manassas, VA, USA). HCEC was cultured in Dulbecco’s modified Eagle’s medium and Ham’s F12 medium containing 10% fetal bovine serum and 1% penicillin–streptomycin. Briefly, HECE was seeded onto a 96-well plate with a density of 6,000 cells per well and incubated overnight. Then, fresh cell culture media containing a series of concentrations (10, 20, 40 μg·mL−1, Zn2+ equivalent) of Zn2+ or ZGNC were added and incubated with the cells for 24 h, respectively. 20 μL of MTT (5 mg·mL−1) was then added to each well and the cells were further cultured at 37°C for another 4 h. Finally, 150 μL of DMSO was added to each well to replace the culture medium and formazan absorbance was determined by a microplate Bio-Rad reader (Thermo Fisher Scientific, Waltham, MA) at 490 nm. Data were presented as average ± standard deviation (n = 4).

2.11 In vitro reactive oxygen species (ROS) depletion ability of ZGNC

Intracellular ROS levels were investigated using DCFH-DA as a fluorescent probe. HCECs were seeded into 24-well plates at a density of 2 × 104 cells per well. After 24 h of incubation, the culture medium was replaced, and the cells were treated with 200 μL of H2O2 (0.1 mM) for 15 min to induce oxidative stress. Subsequently, 50 μL of GA (40.7 μg·L−1), PLL (48.9 μg·L−1), Zn2+ (10.4 μg·L−1), or ZGNC (100 μg·L−1) were added to each well and incubated for another 30 min. The cells were then stained with DCFH-DA and immediately imaged using fluorescent microscopy to visualize and quantify intracellular ROS levels.

2.12 The establishment of a murine bacterial keratitis model

All animal experiments conducted in this study adhered to the “Principles of Laboratory Animal Care” (NIH publication no. 86-23, revised 1985) and were approved by the Institutional Animal Care and Use Committee, Zhejiang Center of Laboratory Animals (ZJCLA), following the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Female C57BL/6 mice weighing 18–20 g were anesthetized using isoflurane. The corneas of the right eyes were scratched with a needle and inoculated with 10 µL of MRSA suspension (approximately 108 CFU·mL−1). After 24 h post-infection, the MRSA-induced keratitis model was successfully established.

2.13 Intraocular retention of ZGNC

To measure the remaining Zn2+ at the corneal site, 2 μL of ZGNC (1 mg·mL−1 Zn2+ equivalent) or Zn2+ (1 mg·mL−1) was administered as eye drops onto the infected corneas. The corresponding mice were euthanized at different time points (1, 4, 8, 12, and 24 h) for analysis of Zn2+ concentration in the corneas using ICP-MS.

2.14 In vivo antibacterial effect of ZGNC

The MRSA-induced keratitis model was established 24 h after infection (Day 0). The infected mice were randomly divided into three groups (n = 3) and received a single dose of different treatments as eye drops including 5 µL H2O, free Zn2+ (1 mg·mL−1), and ZGNC (1 mg·mL−1 Zn2+ equivalent). The morphology of corneas was recorded with a slit-lamp micrograph on Day 0, Day 1, and Day 3. The clinical scores (0–12) for each treated group based on three criteria (area of corneal opacity, density of opacity, and surface regularity, 0–4 for each option) were recorded. On Day 3, the corneas of mice were harvested for MRSA counting.

2.15 Statistical analysis

The statistical difference in clinical scores was analyzed by the Friedman test. The other statistical differences were analyzed by Student’s t-test and one-way analysis of variance with Tukey’s post hoc test. The p-values (p) are indicated as: n.s. (p > 0.05), *(p < 0.05), **(p < 0.01), and ***(p < 0.001).

3 Results and discussion

3.1 Preparation and characterization of ZGNC

Taking advantage of the metal-polyphenol interaction, a zinc–gallic acid nanocomplex (ZGNC) was prepared as the nanocarrier of Zn2+ by the self-assembly of Zn2+, GA, and PLL. To prepare ZGNC, Zn2+, GA, and PLL were dissolved in the mixed solvent of water and ethanol. Ammonia was then added to induce the coordination of Zn2+ and GA. By controlling the feed ratio of Zn2+, GA, and PLL, spherical nanocomplexes could be obtained after centrifugation. As shown in the TEM image in Figure 2a, ZGNC showed well-dispersed spherical morphologies. The size of ZGNC measured by TEM was about 162.1 nm. The elemental distribution in ZGNC was then investigated by EDS mapping on a high-resolution TEM. As depicted in Figure 2b, all the elements including Zn, C, N, and O were homogeneously distributed in ZGNC. Since ZGNC was prepared in a basic environment, it was important to know how if crystallized ZnO nanoparticles were obtained. The crystallinity of ZGNC was then explored by XRD analysis. Interestingly, a typical sharp crystal diffraction peak was not observed in the XRD spectrogram of ZGNC, indicating the amorphous structure of ZGNC (Figure 2c). The interaction of Zn2+, GA, and PLL in ZGNC was further investigated by XPS analysis. The standard binding energy of Zn2+ 2p3/2 is 1,023.0 eV (35). However, the binding energy of Zn2+ 2p3/2 in ZGNC was 1,021.6 eV, 1.4 eV lower than the standard value, which implied that Zn in ZGNC received electrons from electron donors such as N and O (Figure 2d). Therefore, Zn in ZGNC could form a coordination structure with N and O. Meanwhile, the N element in PLL exhibited two peaks, 401.2 eV for the N1s band of primary amine and 399.7 eV for the N1s band of secondary amine (25). However, only the N1s band of secondary amine was observed in the N1s XPS spectrum of ZGNC (Figure 2e). The disappearance of the N1s band of a primary amine in ZGNC indicated that the –NH2 groups in PLL provided electron pairs to Zn2+ to obtain coordination structures. Therefore, ZGNC was prepared probably owing to the coordination self-assembly of Zn2+, GA, and PLL. The intensity-average hydrodynamic diameter of ZGNC was 195.2 nm with a polydispersity index of 0.175 (Figure 2f). Due to the presence of cationic polymer PLL, the zeta potential of ZGNC was +35.0 mV, which was very important for the efficient adhesion to negatively charged bacterial cells. The loading content of Zn2+ in ZGNC was 10.4% determined by ICP-MS. The content of GA in ZGNC was about 40.7% measured by high-performance liquid chromatography.

Figure 2 Characterization of ZGNC. (a) The TEM image of ZGNC. (b) Elemental distribution of C, N, O, and Zn in ZGNC measured by EDS mapping on a high-resolution TEM. HAADF: high angle annular dark field. (c) The XRD spectrogram of ZGNC. (d) The XPS spectrum of Zn2p in ZGNC. (e) The XPS spectra of N1s in ZGNC and PLL. (f) The intensity-average hydrodynamic diameter of ZGNC measure by DLS. (g) The TEM image of ZGNC after incubating at pH 6.5. (h) The release of Zn2+ from ZGNC at pH 7.4 and 6.5.
Figure 2

Characterization of ZGNC. (a) The TEM image of ZGNC. (b) Elemental distribution of C, N, O, and Zn in ZGNC measured by EDS mapping on a high-resolution TEM. HAADF: high angle annular dark field. (c) The XRD spectrogram of ZGNC. (d) The XPS spectrum of Zn2p in ZGNC. (e) The XPS spectra of N1s in ZGNC and PLL. (f) The intensity-average hydrodynamic diameter of ZGNC measure by DLS. (g) The TEM image of ZGNC after incubating at pH 6.5. (h) The release of Zn2+ from ZGNC at pH 7.4 and 6.5.

The rapid and efficient release of metal ions is very important for metal ion-based delivery systems. The MPN was unstable and could be dissociated in an acidic environment, which might lead to the disassembly of ZGNC. As expected, spherical nanoparticles could not be observed anymore after ZGNC was incubated at pH 6.5 (Figure 2g). After ZGNC was dissociated at pH 6.5, Zn2+ in ZGNC would be released rapidly. As shown in Figure 1h, more than 50% of Zn2+ could be released from ZGNC after incubating at pH 6.5 for 1 h, implying rapid release of Zn2+ in acidic infected microenvironment. However, ZGNC was relatively stable at pH 7.4. Since PBS was used in the drug release experiment, 17.8% Zn2+ could be released after 6 h incubation, probably owing to the disturbance of the coordination interaction by abundant anions in PBS.

3.2 In vitro bactericidal activity of ZGNC

Zn2+ is a well-known broad-spectrum bactericidal agent (36). The in vitro bactericidal property of ZGNC was investigated by the standard colony counting assay using Gram-positive MRSA and Gram-negative E. coli as model strains. First, the antibacterial activity of ZGNC was evaluated by incubating with about 108 CFU mL–1 bacteria for 6 h at pH 7.4. As shown in Figure 3a, ZGNC with 15 μg·mL−1 Zn2+ equivalent could induce 3.1 orders of magnitude reduction of MRSA, which exhibited much better bactericidal activity than free Zn2+ (1.5 orders of magnitude reduction of MRSA). Meanwhile, ZGNC with 15 μg·mL−1 Zn2+ equivalent induced 4.4 orders of magnitude reduction of MRSA after incubation for 6 h at pH 6.5, which exhibited much better bactericidal activity than that at pH 7.4, probably owing to the rapid release of Zn2+ from ZGNC in an acidic environment (Figure 3b). ZGNC also exhibited excellent bactericidal activity against E. coli at both pH 7.4 and 6.5 (Figure 3c and d), with 2.8 and 4.6 orders of magnitude reduction of E. coli, respectively (15 μg·mL−1 Zn2+ equivalent). It should be noted that ZGNC also exhibited much better bactericidal activity against E. coli than free Zn2+. Therefore, the formation of ZGNC significantly enhanced the bactericidal activity of Zn2+.

Figure 3 The characterization of in vitro bactericidal ability of ZGNC. (a) The bactericidal ability of ZGNC, Zn2+, and PLL against MRSA at pH 7.4. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (b) The bactericidal ability of ZGNC, Zn2+, and PLL against MRSA at pH 6.5. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (c) The bactericidal ability of ZGNC, Zn2+, and PLL against E. coli at pH 7.4. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (d) The bactericidal ability of ZGNC, Zn2+, and PLL against E. coli at pH 6.5. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (e) The bactericidal ability of ZGNC, Zn2+, and PLL against MRSA in BSA solution. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (f) The bactericidal ability of ZGNC, Zn2+, and PLL against E. coli in BSA solution. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (g) Plates images of MRSA and E. coli after incubation with ZGNC, Zn2+, and PLL. (h) The viability of HCECs after incubation with ZGNC and Zn2+ measured by MTT. “10, 20, and 40 μg·mL−1” refers to Zn2+ equivalent. The p-values are indicated as: n.s. (p > 0.05), *(p < 0.05), **(p < 0.01), and ***(p < 0.001).
Figure 3

The characterization of in vitro bactericidal ability of ZGNC. (a) The bactericidal ability of ZGNC, Zn2+, and PLL against MRSA at pH 7.4. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (b) The bactericidal ability of ZGNC, Zn2+, and PLL against MRSA at pH 6.5. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (c) The bactericidal ability of ZGNC, Zn2+, and PLL against E. coli at pH 7.4. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (d) The bactericidal ability of ZGNC, Zn2+, and PLL against E. coli at pH 6.5. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (e) The bactericidal ability of ZGNC, Zn2+, and PLL against MRSA in BSA solution. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (f) The bactericidal ability of ZGNC, Zn2+, and PLL against E. coli in BSA solution. The concentration of PLL in the PLL group was the same as that in the ZGNC group. (g) Plates images of MRSA and E. coli after incubation with ZGNC, Zn2+, and PLL. (h) The viability of HCECs after incubation with ZGNC and Zn2+ measured by MTT. “10, 20, and 40 μg·mL−1” refers to Zn2+ equivalent. The p-values are indicated as: n.s. (p > 0.05), *(p < 0.05), **(p < 0.01), and ***(p < 0.001).

Zn2+ is known to lose its bactericidal ability in a protein-rich environment due to the adsorption by proteins (33). It is interesting to know if ZGNC could maintain its bactericidal activity in a protein-rich environment. The bactericidal property of ZGNC was then assessed in BSA solution. The antibacterial effect of ZGNC and free Zn2+ in 5 mg·mL−1 BSA solution is shown in Figure 3e and f. As expected, free Zn2+ completely lost its bactericidal ability against MRSA and E. coli in the BSA solution. Surprisingly, ZGNC exhibited excellent bactericidal ability against MRSA in BSA solution, with 2.5 orders of magnitude reduction of MRSA (15 μg·mL−1 Zn2+ equivalent). The excellent bactericidal ability of ZGNC against E. coli was also confirmed in the BSA solution. Therefore, ZGNC could effectively kill both Gram-positive and Gram-negative bacteria in the protein-rich solution (Figure 3g). The outstanding bactericidal ability of ZGNC in the protein-rich solution might be ascribed to the effective adhesion of ZGNC onto bacterial cells, which could effectively avoid the inactivation of Zn2+ by proteins. Actually, it is inevitable that ZGNC will contact with proteins if it is used in vivo. The outstanding bactericidal ability of ZGNC in protein-rich solution is extremely important for its in vivo applications. The potential cytotoxicity of metal ions is another critical issue for in vivo use. HCECs were used to evaluate the cytotoxicity of ZGNC. As shown in Figure 3h, ZGNC did not exhibit obvious cytotoxicity when the Zn2+ equivalent concentration was as high as 40 μg·mL−1, while more than 90% MRSA could be eradicated when the Zn2+ equivalent concentration of ZGNC was 10 μg·mL−1, exhibiting great promise for in vivo antibacterial use of ZGNC.

3.3 Potential mechanism for enhanced bactericidal activity of ZGNC

Based on the excellent bactericidal activity of ZGNC, the potential bactericidal mechanism was then investigated. Since ZGNC was positively charged and bacterial cells were negatively charged, we investigated if ZGNC could adhere to bacterial cells. At present, more than 75% of bacterial keratitis in China is induced by Gram-positive bacteria, such as S. aureus. Therefore, MRSA was used as the model strain in the following experiments. After MRSA was incubated with FITC-labeled ZGNC (FITC-ZGNC), the obvious overlap of DAPI-stained MRSA and FITC-ZGNC was observed by fluorescent imaging, indicating efficient adhesion of ZGNC onto bacterial cells (Figure 4a).

Figure 4 (a) The fluorescent imaging of DAPI-stained MRSA after incubation with FITC-labeled MRSA. (b) The K+ concentration in the culture medium after MRSA was incubated with ZGNC at pH 7.4 and 6.5. (c) The SEM images of MRSA after incubation with ZGNC, Zn2+, and PLL. The p-values are indicated as: n.s. (p > 0.05), *(p < 0.05), **(p < 0.01), and ***(p < 0.001).
Figure 4

(a) The fluorescent imaging of DAPI-stained MRSA after incubation with FITC-labeled MRSA. (b) The K+ concentration in the culture medium after MRSA was incubated with ZGNC at pH 7.4 and 6.5. (c) The SEM images of MRSA after incubation with ZGNC, Zn2+, and PLL. The p-values are indicated as: n.s. (p > 0.05), *(p < 0.05), **(p < 0.01), and ***(p < 0.001).

After MRSA was treated with ZGNC, the morphological change in bacterial cells was studied by SEM. As shown in Figure 4c, an intact bacterial membrane was observed in normal MRSA. However, collapsed morphology was observed in some MRSA after incubation with Zn2+ owing to the intrinsic bactericidal activity of ZGNC. After MRSA was incubated with ZGNC, obvious adhesion of ZGNC on MRSA could be observed in the SEM image. Serious damage to bacterial cells could also be observed after incubating MRSA with ZGNC. The damage to bacterial cells could induce the leakage of components inside bacterial cells. The leakage of K+ was then investigated by measuring K+ concentration in the culture medium after MRSA was incubated with ZGNC at pH 7.4 and pH 6.0. As expected, the leakage of K+ was greatly enhanced after MRSA was incubated with ZGNC (Figure 4b). Therefore, after ZGNC was incubated with MRSA, ZGNC could effectively adhere to bacterial cells and release Zn2+ very close to bacterial cells, which significantly enhanced the localized concentration of Zn2+ surrounding bacterial cells, leading to enhanced bactericidal activity of ZGNC. The surrounding Zn2+ could damage bacterial membranes and induce the leakage of intracellular components, finally resulting in bacterial death.

3.4 ROS-scavenging ability of ZGNC

Bacterial infection can induce serious inflammation, leading to the generation of abundant ROS (37). The excess, highly reactive ROS are fatal if not consumed timely, resulting in lipids oxidation, protein denaturation, DNA dysfunction, and finally inducing the death of normal cells. Therefore, to relieve inflammation, timely depletion of excess ROS is very important. As an important polyphenol, GA exhibits strong antioxidant ability by depleting ROS. We then investigated if ZGNC could deplete intracellular ROS using DCFH-DA as a ROS fluorescent probe. As depicted in Figure 5, the intracellular ROS level was greatly elevated after HCECs were incubated with 100 μM of H2O2. However, the intracellular green fluorescence of the ROS probe was remarkably reduced after incubating with ZGNC, which indicated that intracellular ROS could be effectively depleted by ZGNC due to the strong antioxidant ability of GA.

Figure 5 The fluorescent images of HCECs with different treatments using DCFH-DA as the ROS fluorescent probe.
Figure 5

The fluorescent images of HCECs with different treatments using DCFH-DA as the ROS fluorescent probe.

3.5 In vivo bactericidal ability of ZGNC on a murine bacterial keratitis model

Encouraged by the outstanding bactericidal ability of ZGNC in vitro, we further investigated the bactericidal ability of ZGNC in vivo. A murine MRSA-induced keratitis model was established to evaluate the bacterial potential of ZGNC in vivo. Effective intraocular drug retention is very important for eye drops. Owing to the electrostatic interaction between ZGNC and bacterial cells, the intraocular retention of ZGNC was studied. The bacterial keratitis model was established by inoculating MRSA onto the scratched corneas. ZGNC or free Zn2+ was administrated as eye drops 24 h post-infection. Intraocular Zn2+ concentration was measured by ICP-MS at different time intervals. As shown in Figure 6a, ZGNC exhibited much longer intraocular retention than free Zn2+, which was very important for the enhanced bactericidal ability of ZGNC in treating bacterial keratitis.

Figure 6 The in vivo bactericidal ability of ZGNC evaluated on a murine MRSA-induced keratitis model. (a) The intraocular Zn2+ retention after being treated with ZGNC and free Zn2+ for different time intervals. (b) Slit-lamp photos of murine eyeballs after different treatments on Day 0, Day 1, and Day 3. ZGNC and Zn2+ were administrated on Day 0 (24 post-infection). (c) Eye clinical scores after different treatments on Day 0, Day 1, and Day 3. (d) MRSA colony counting of corneal tissue after different treatments on Day 3. The p-values are indicated as: n.s. (p > 0.05), *(p < 0.05), **(p < 0.01), and ***(p < 0.001).
Figure 6

The in vivo bactericidal ability of ZGNC evaluated on a murine MRSA-induced keratitis model. (a) The intraocular Zn2+ retention after being treated with ZGNC and free Zn2+ for different time intervals. (b) Slit-lamp photos of murine eyeballs after different treatments on Day 0, Day 1, and Day 3. ZGNC and Zn2+ were administrated on Day 0 (24 post-infection). (c) Eye clinical scores after different treatments on Day 0, Day 1, and Day 3. (d) MRSA colony counting of corneal tissue after different treatments on Day 3. The p-values are indicated as: n.s. (p > 0.05), *(p < 0.05), **(p < 0.01), and ***(p < 0.001).

The therapeutic efficacy of ZGNC in treating bacterial keratitis was then studied. The mice infected by bacterial keratitis were randomly divided into three groups and received different formulations 24 h post-infection, including H2O, free Zn2+, and ZGNC, respectively. The therapeutic efficacy was intuitively observed by a slit-lamp microscopy (Figure 6b). Severe corneal lesions were observed 24 h post-infection (Day 0 before treatment), including swelling, congestion, opacity, and exudation, with clinical scores nearly reaching 10 points for all groups (Figure 6c). After 3 days’ treatment with ZGNC, corneal infection was significantly alleviated with relatively clear eyeballs. The clinical score of the ZGNC-treated group dropped to 2.8 points. However, serious infection could still be observed in the Zn2+ treated groups. The ocular residual MRSA after different treatments was measured by a standard plate count method on the third day post-treatment. ZGNC eradicated more than 99.9% of MRSA from the cornea, while free Zn2+ was almost invalid in eradicating MRSA (Figure 6d), which implied the great potential of ZGNC in treating internal bacterial infections.

4 Conclusions

In conclusion, zinc–gallic acid nanocomplexes (ZGNC) were prepared by coordinating the self-assembly of Zn2+, GA, and PLL, which could achieve efficient delivery and rapid release of Zn2+. The coordination interaction in ZGNC was fully verified by XPS. ZGNC were spherical nanoparticles with a size of 162.1 nm. ZGNC were stable in the physiological environment (pH 7.4). However, ZGNC could be dissociated in a mild acidic environment (pH 6.5), leading to the rapid release of Zn2+. More than 50% Zn2+ could be released within 1 h after incubating ZGNC at pH 6.5. ZGNC were positively charged and could be adhered onto bacterial cells, which played a critical role in the outstanding bactericidal activity of ZGNC. ZGNC exhibited much better bactericidal ability than free Zn2+ against both Gram-positive and Gram-negative bacteria. More importantly, ZGNC could effectively avoid the deactivation of Zn2+. Therefore, ZGNC maintained excellent bactericidal activity in the BSA solution, while free Zn2+ is completely invalid to eradicate bacteria in the BSA solution. ZGNC did not show obvious cytotoxicity when the Zn2+ equivalent was 40 μg·mL−1. A murine MRSA-induced keratitis model was established to evaluate the in vivo bactericidal ability of ZGNC. Owing to the strong electrostatic interaction between ZGNC and MRSA, ZGNC showed much longer intraocular retention than free Zn2+. Therefore, ZGNC eradicated more than 99.9% of MRSA from the cornea, while free Zn2+ was almost invalid in eradicating MRSA, which confirmed the feasibility of ZGNC for in vivo antibacterial applications. ZGNC could be considered a promising metal ion delivery nanoplatform in treating internal bacterial infections.

Acknowledgements

Kaijun Li and Ya Zhang are co-first authors and contributed equally to this work. Thanks to Yonghong Chen from Chengdu Aochuang Biotechnology Co., Ltd. for her valuable support in the cytotoxicity study.

  1. Funding information: This work was supported by the program of Chengdu Science and Technology Bureau (2024-YF05-00431-SN) and Aier Eye Hospital-Sichuan University (grant numbers 23JZH044).

  2. Author contributions: Kaijun Li: visualization, project administration, funding acquisition, and writing – original draft. Ya Zhang: visualization, methodology, data curation, and formal analysis. Kaihui Cheng: data curation and formal analysis. Chengcheng Wu: data curation and formal analysis. Qiao Jin: conceptualization and resources. Ling Yu: supervision, methodology writing – review and editing, and formal analysis.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2024-12-19
Revised: 2024-12-28
Accepted: 2025-01-10
Published Online: 2025-03-10

© 2025 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/epoly-2024-0115
Keywords for this article
antibacterial; metal ion delivery system; metal-phenolic network; coordination interaction; bacterial keratitis
Creative Commons
BY 4.0

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  1. Research Articles
  2. Flow-induced fiber orientation in gas-powered projectile-assisted injection molded parts
  3. Research on thermal aging characteristics of silicone rubber composite materials for dry-type distribution transformers
  4. Kinetics of acryloyloxyethyl trimethyl ammonium chloride polymerization in aqueous solutions
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