Silica meets flavonoid: zwitterionic silica–quercetin nanocarriers embedded in electrospun fibers for wound healing

Nesrin Horzum; Fatma Rabia Karaduman; Sena Nur Köksal; Aslı Eldem; Özlem Karakoç; Ayşegül Ülkü Metin

doi:10.1039/d6na00563b

. 2026 Oct 21. Online ahead of print. doi: 10.1039/d6na00563b

Silica meets flavonoid: zwitterionic silica–quercetin nanocarriers embedded in electrospun fibers for wound healing

Nesrin Horzum ^a, Fatma Rabia Karaduman ^b, Sena Nur Köksal ^b, Aslı Eldem ^c, Özlem Karakoç ^b, Ayşegül Ülkü Metin ^b,^✉

PMCID: PMC13721908 PMID: 42965110

Abstract

Silica-based nanomaterials are widely applied in biomedicine; however, achieving stable bioactive functionalization and integrating multiple therapeutic functions within a single material remain important challenges. Herein, we report the fabrication of multifunctional zwitterion-grafted silica nanoparticles loaded with quercetin (Zw-SiNPs@Q) and their incorporation into electrospun poly(vinyl alcohol)/poly(acrylic acid) (PVA–PAA) nanofibers to create bioactive hybrid wound dressings. The distinctive feature of this approach is the use of Zw-grafted SiNPs as an intermediate nanoengineered interface for Q immobilization before their incorporation into the electrospun matrix, rather than directly blending the bioactive molecule with the polymer. Zwitterionic polymer chains were covalently grafted onto the surfaces of SiNPs via radical copolymerization, followed by Q functionalization. Structural and compositional analyses confirmed successful stepwise surface modification while preserving nanoparticle morphology. The resulting Zw-SiNPs@Q/PVA–PAA nanofibers exhibited sustained and concentration-dependent Q release over 72 h without a pronounced burst effect, highlighting the ability of the nanoengineered interface to serve as a reservoir for localized prolonged Q delivery. The hybrid nanofibers demonstrated strong antioxidant activity and concentration-dependent antibacterial effects against both E. coli and S. aureus, with complete bacterial inhibition observed in pre-annealed samples. The materials also exhibited excellent cytocompatibility, maintaining >80% viability in L929 fibroblasts. In an LPS-induced inflammatory model, Zw-SiNPs@Q3.2/PVA–PAA nanofibers significantly downregulated pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) while upregulating IL-10 and TGF-β, indicating a shift toward a pro-resolving microenvironment. Scratch wound-healing assays further revealed accelerated wound closure, with wound gaps reduced to ∼30% at 72 h compared to ∼60% in controls. By integrating a zwitterionic nanoengineered interface with sustained Q delivery, antioxidant activity, and immunomodulatory effects, this study yields a multifunctional nanofibrous platform that addresses biological processes relevant to wound healing. These findings establish Zw-SiNPs@Q/PVA–PAA nanofibers as a promising bioactive interface for advanced wound management and tissue repair applications.

1. Introduction

Nanoparticles have attracted significant attention in biomedical and functional materials because of their tunable size, large surface area, and versatile surface chemistry.^1,2 Among various nanostructured materials, silica nanoparticles (SiNPs) have attracted considerable attention because of their remarkable chemical stability, excellent biocompatibility, and ease of functionalization. These characteristics make them highly suitable carriers for bioactive molecules or functional modifiers in polymeric matrices.^2,3 Despite these advantages, the direct application of SiNPs can be limited by their inherent abrasiveness⁴ and surface-related interactions, necessitating appropriate surface modification strategies to improve their interfacial functionality, stability, and biocompatibility.^5,6 Surface engineering approaches, such as polymer grafting or biomolecular conjugation, can tailor the physicochemical properties of SiNPs by introducing functional groups and modulating their interactions with the surrounding environments.^7–10 Such modifications can also enable the immobilization and controlled delivery of bioactive molecules, making surface-functionalized SiNPs attractive components of multifunctional nanocomposite systems. Among these strategies, grafting polymer brushes onto SiNP surfaces has emerged as a particularly effective approach.¹¹ Polymer brushes enable precise control over interfacial, mechanical, thermal, and biological properties, thereby making nanoparticles more compatible with complex physiological environments.^12–14 A notable example is poly(2-(methacryloyloxy)ethyl)dimethyl-(3-sulfopropyl)ammonium hydroxide (DMAPS, also known as sulfobetaine methacrylate, SBMA), a zwitterionic, nonfouling polymer valued for its stable physicochemical properties across a wide pH range and long-term commercial reliability.^15–17

Polymerized SBMA (PSBMA) forms hydrated brush layers that have been widely reported to impart antifouling characteristics, reduced protein adsorption, excellent thermal stability, and lubrication on SiNP surfaces.^4,17,18 A critical factor influencing its interfacial performance is the formation of a polymer brush layer, whose properties depend strongly on the layer's thickness. While an optimal thickness promotes the formation of a hydrophilic, hydrated interface, exceeding this limit can cause a wettability transition and increased hydrophobicity.¹⁹ Thus, PSBMA serves as a versatile functional building block for designing lubricious and antifouling surfaces in biomedical and materials science applications. Grafting SBMA via atom transfer radical polymerization or photopolymerization has been reported to enhance nanoparticle stability, reduce nonspecific interactions, and facilitate tunable, stimuli-responsive surface behavior.^20,21 Such functionalized nanoparticles exhibit markedly reduced protein adhesion, including fibronectin and albumin adsorption, as well as improved tribological performance.^4,22

Building on the favorable interfacial properties reported for PSBMA-functionalized nanoparticles, zwitterionic polymers have attracted increasing attention for surface modification. These polymers contain both positively and negatively charged groups and form strongly hydrated interfaces that can reduce nonspecific protein adsorption and bacterial attachment.^17,22–26 These characteristics make zwitterionic modification an attractive strategy for tailoring nanoparticle–biointerface interactions. However, zwitterionic modification alone does not necessarily provide bactericidal or antioxidant activity, motivating its combination with complementary bioactive agents.^27,28 Quercetin (Q), a natural flavonoid, is particularly attractive for biomedical applications because of its potent antioxidant, antimicrobial, and therapeutic properties.²⁹ However, its direct incorporation into polymer matrices often results in poor stability and uneven distribution. Therefore, stable conjugation of Q to nanoparticles is crucial to maintain long-term bioactivity and ensure effective surface modification. Functionalizing zwitterionic polymer-coated silica nanoparticles (Zw-SiNPs) with Q (Zw-SiNPs@Q) can stabilize the bioactive molecule, preserve its activity, and achieve uniform distribution within composite materials. This strategy produces nanoparticles with enhanced antimicrobial and antioxidant properties, effectively addressing the limitations of conventional polymer-modified surfaces. To further leverage these enhanced functionalities in practical biomedical applications, Zw-SiNPs@Q can be incorporated into advanced material platforms such as electrospun nanofibers.

Nanofibers are highly versatile materials with nanoscale diameter, high surface-to-volume ratios, and interconnected porous structure. These features make them particularly suitable for biomedical applications such as wound dressings, tissue-engineering scaffolds, drug delivery systems, and implantable devices, as their architecture closely mimics the extracellular matrix (ECM) and promotes cell adhesion, proliferation, and differentiation.^30–33 Electrospinning enables the fabrication of nanofibers from a wide range of natural and synthetic polymers, enabling precise control over mechanical strength, hydrophilicity, biodegradability, and surface functionality.³⁴ Common polymers include biocompatible synthetic polymers such as polyvinyl alcohol (PVA), polycaprolactone (PCL), poly(lactic acid) (PLA), and poly (lactic-co-glycolic acid) (PLGA), as well as natural polymers like gelatin, chitosan, silk fibroin, and collagen.³⁵ The polymer choice strongly influences biodegradability, hydrophilicity, and cellular interactions, which are crucial for biomedical applications.

PVA is a nontoxic, water-soluble polymer widely used in electrospinning because of its good spinnability, fiber-forming ability, and cytocompatibility.^36–38 However, its high water solubility limits the use of electrospun PVA alone in aqueous environments.^39,40 Poly(acrylic acid) (PAA) was therefore blended with PVA to provide complementary carboxylic acid (–COOH) groups that can interact with the hydroxyl (–OH) groups of PVA. Upon thermal treatment, these functional groups undergo intermolecular esterification, forming a crosslinked PVA/PAA network with improved resistance to dissolution in aqueous media.^40,41 Thus, PVA primarily provides the electrospinnable fiber-forming matrix, whereas PAA provides carboxyl functionality for thermal crosslinking and contributes to interactions within the composite network. This complementary combination was selected instead of either polymer alone to obtain an electrospinnable, hydrophilic nanofibrous scaffold with improved resistance to aqueous dissolution through thermal crosslinking, without the use of an additional chemical crosslinker. The fabrication of nanocomposites is a prominent strategy for introducing additional functionality into nanofibrous matrices. Specifically, incorporating bioactive nanoparticles can impart functionalities such as antimicrobial and antioxidant activities, thereby expanding their potential for biomedical applications.⁴² The physicochemical properties of PVA/PAA nanofibers can be further tailored by incorporating nanofillers such as carbon nanotubes,³⁹ boron nitride,^41,43 silica nanoparticles,^44,45 or montmorillonite.⁴⁶ These additives can modify the mechanical, thermal, and functional characteristics of the nanofibers, broadening their potential for advanced biomedical and environmental applications.^47,48 Among these, SiNPs are particularly attractive because their surface silanol groups provide a versatile platform for further functionalization with polymers and bioactive molecules. Despite significant progress in developing electrospun nanocomposite systems, several key challenges remain unaddressed. The stability of bioactive molecules such as Q on polymeric surfaces is often compromised by oxidation, photodegradation, or weak physical adsorption, thereby reducing long-term functionality. Furthermore, achieving homogeneous nanoparticle dispersion within polymer matrices remains a significant limitation, as nanoparticle aggregation can disrupt fiber morphology and reduce performance uniformity. While zwitterionic polymer coatings have been widely investigated for their interfacial and biointerface properties, systematic studies on their integration into electrospun nanofiber systems remain limited. In the present design, Zw modification was introduced at the nanoparticle level rather than directly on the nanofiber surface.

The purpose of this modification was to create a functional nano-interface for Q immobilization before incorporation into the PVA/PAA matrix. Thus, Zw-SiNPs@Q were designed to act as embedded bioactive nanocarriers within the electrospun scaffold rather than as a continuous zwitterionic coating on the external nanofiber surface. The surrounding PVA/PAA network provides a thermally crosslinked nanofibrous framework and an additional diffusion barrier, while allowing aqueous penetration and diffusion-mediated release of Q from the incorporated nanocarriers. Building on this design rationale, the present study introduces a hierarchical nanoengineered strategy that integrates three functional levels within a single material: Zw surface modification of SiNPs, immobilization of the bioactive flavonoid Q on the modified nanoparticles, and incorporation of the resulting Zw-SiNPs@Q into a thermally crosslinked electrospun PVA/PAA matrix. In this design, the zwitterionic SiNP interface serves as a bioactive nanocarrier and reservoir for Q, while the thermally crosslinked PVA/PAA nanofibrous network provides the supporting scaffold and an additional diffusion barrier for sustained Q release. To the best of our knowledge, the integration of Zw-SiNPs@Q into electrospun PVA/PAA nanofibers and its combined evaluation for sustained Q delivery, antibacterial and antioxidant activity, inflammatory regulation, and fibroblast migration has not been comprehensively reported. Accordingly, the novelty of this work lies in constructing a multifunctional nanoengineered platform that integrates sustained bioactive delivery with multiple biological functions relevant to wound healing. Therefore, this study aims to develop and characterize electrospun PVA/PAA nanofibers embedded with Zw-SiNPs@Q. The primary objectives are to: (i) synthesize and functionalize SiNPs with zwitterionic polymer brushes and Q, (ii) fabricate Zw-SiNPs@Q-incorporated PVA/PAA nanofibers via electrospinning and thermal crosslinking, and (iii) evaluate their physicochemical and biological properties.

2. Materials and methods

2.1. Materials

Tetraethyl orthosilicate (TEOS, Si(OC₂H₅)₄; ≥99.0%; Germany), [2-(methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide (DMAPS, H₂C C(CH₃)CO₂CH₂CH₂N(CH₃)₂(CH₂)₃SO₃; ≥95.0%; USA), 2,2′-azobis(2-methylpropionitrile) (AIBN, ≥98.0%; China), and quercetin (Q; ≥95.0%; USA) were purchased from Sigma-Aldrich. Absolute ethanol and ammonia solution (25 wt% NH₃ in water) were obtained from Merck (Germany). Poly(vinyl alcohol) (PVA, Mn ≈ 30 000–70 000 g mol⁻¹, 87–90% hydrolyzed; Sigma-Aldrich, USA) and poly(acrylic acid) (PAA, Mw: 100 000 g mol⁻¹; 35 wt% in water; Sigma-Aldrich, Germany) were used in this study. The countries indicated for the materials refer to the countries of origin reported by the respective suppliers.

2.2. Synthesis of silica nanoparticles

Silica nanoparticles (SiNPs) were synthesized by homogenizing ethanol (47.0 mL), deionized water (3.0 mL), and tetraethyl orthosilicate (TEOS, 3.0 mL) for 10 min, following previously reported methods.^49,50 Subsequently, ammonia solution (25% wt, 3.0 mL) was added, and the mixture was stirred. The resulting particles were collected by centrifugation, washed with ethanol and deionized water, then dried at room temperature.

2.3. Grafting of zwitterionic polymer on SiNPs

SiNPs (100 mg) were dispersed in deionized water (10 mL) and heated for 20 min in a thermostatic water bath at 70 °C under a low-flow nitrogen atmosphere. Subsequently, AIBN (25 mg) and [2-(methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide (DMAP, 500 mg) were added, and the reaction was carried out at 70 °C for 4 h.⁵¹ After completion, DMAP-grafted silica nanoparticles (Zw-SiNPs) were obtained by cooling the reaction mixture to room temperature and precipitating with cold acetone. To evaluate the effect of initiator or monomer concentration on grafting efficiency, experiments were also conducted with different amounts of AIBN (25 and 50 mg) and DMAP (250 mg and 500 mg). Grafting yield was calculated using the following equation, where m_g is the weight of the grafted copolymer and m_c is the weight of the monomer used.

2.4. Functionalization of zwitterionic polymer-coated SiNPs with Q

To impart antioxidant functionality, Q was utilized to modify Zw-SiNPs. Briefly, Q (20 mg) was dissolved in ethanol (1 mL) and mixed with Zw-SiNPs (20 mg) at room temperature. After the solvent evaporated completely, the obtained product (Zw-SiNPs@Q) was sequentially washed with ethanol and distilled water, then dried at room temperature.⁵²

2.5. Engineering PVA–PAA nanofibers reinforced with bioactive Zw-SiNPs@Q

PVA–PAA nanofibers containing Zw-SiNPs@Q were fabricated using an electrospinning system (Inovenso Basic Set-up, Inovenso, Türkiye), with minor modifications to a previously reported method.⁵³ Briefly, 3.5 g of PVA was dissolved in 28.0 mL of deionized water under magnetic stirring for 3 h at room temperature. The PAA solution was diluted with deionized water to obtain a 10% (w/v) concentration. Subsequently, 2 mL of the PVA solution was mixed with 1 mL of the PAA solution to obtain the PVA–PAA blend. Hybrid nanofillers (Zw-SiNPs@Q) were then incorporated into the PVA–PAA blend at different amounts of 15, 30, 50, and 100 mg. Each formulation was sonicated in an ultrasonic bath at 180 W for 15 min and then magnetically stirred at room temperature for 2 h to ensure homogeneous dispersion of the nanofillers. The resulting formulations were designated as Zw-SiNPs@Q0.5, Zw-SiNPs@Q1.0, Zw-SiNPs@Q1.6, and Zw-SiNPs@Q3.2, corresponding to 0.5, 1.0, 1.6, and 3.2% (w/w) Zw-SiNPs@Q relative to the total solution mass, respectively. The weight percentages were calculated based on the combined mass of the PVA solution, PAA solution, and Zw-SiNPs@Q.

For electrospinning, the Zw-SiNPs@Q/PVA–PAA solutions were transferred into a 10 mL plastic syringe fitted with a metallic needle having an inner diameter of 1.0 mm. The syringe was mounted horizontally on a microsyringe pump. Electrospinning was performed at a flow rate of 1.8 mL h⁻¹, an applied voltage of 16 kV, and a tip-to-collector distance of 14 cm. The process was conducted at 24 °C and 51% relative humidity. A total of 3 mL of each Zw-SiNPs@Q/PVA–PAA solution was electrospun onto aluminum foil covering a static collector with an effective collection area of 15 × 20 cm. The thickness of each electrospun mat was measured at three different locations using an optical microscope (Eclipse LV150N, Nikon Corporation, Tokyo, Japan). The mean thickness of the electrospun mats was 50 ± 10 µm. The resulting nanofibers were thermally annealed at 135 °C for 2 h to cross-link the PVA–PAA matrix. Depending on the Zw-SiNPs@Q content, the nanofibers were denoted as PVA/PAA, Zw-SiNPs@Q0.5/PVA–PAA, Zw-SiNPs@Q1.0/PVA–PAA, Zw-SiNPs@Q1.6/PVA–PAA, and Zw-SiNPs@Q3.2/PVA–PAA, respectively.

2.6. Characterization

2.6.1. Morphological and structural characterization Zw-SiNPs@Q nanoparticles and Zw-SiNPs@Q/PVA–PAA composite nanofibers

Crystallographic structures of SiNPs, Zw-SiNPs, and Zw-SiNPs@Q nanoparticles were examined using X-ray diffraction (Bruker AXS/Discovery D8) within a 10–90° range at a scanning rate of 1°/min. The structural features of SiNPs, Zw-SiNPs, and Zw-SiNPs@Q nanoparticles were examined using transmission electron microscopy (TEM; JEM 2100 F, JEOL, Japan). The surface topography of nanoparticles and composite nanofibers was further characterized using scanning electron microscopy (SEM), and elemental compositions were determined using the integrated energy-dispersive X-ray spectroscopy (EDX) system (QUANTA 400 F Field Emission). Average nanoparticle and fiber diameters were calculated from SEM images by measuring at least 100 randomly selected nanoparticles and fibers using the Fiji software. Fourier-transform infrared spectroscopy (FTIR, Shimadzu IRTracer™-100) was employed to characterize SiNPs, Zw-SiNPs, and Zw-SiNPs@Q nanoparticles, as well as PVA/PAA and Zw-SiNPs@Q-modified composite nanofibers.

The thermal behavior of SiNPs, Zw-SiNPs, and Zw-SiNPs@Q nanoparticles and PVA–PAA and Zw-SiNPs@Q/PVA–PAA composite nanofibers was evaluated using thermogravimetric/differential scanning calorimetry (TGA/DSC, TA/SDT650). The water uptake capacity of PVA–PAA and Zw-SiNPs@Q/PVA–PAA composite nanofibers was assessed using gravimetric analysis. Pre-dried and accurately weighed samples were immersed in 10 mL of phosphate-buffered saline (PBS, pH 7.4) at room temperature. The swelling degree was determined according to the following equation: 2.6.1. where W_d and W_s represent the weights of dried and swollen composite fibers, respectively.

Hydrolytic degradation tests were conducted to evaluate nanofiber stability, following the method reported by Díez-Pascual and Díez-Vicente.⁵⁴ PVA–PAA and Zw-SiNPs@Q/PVA–PAA (10 mg) were weighed (W_i) and incubated in PBS (10 mL, pH 7.4) at 37 °C under shaking conditions (100 rpm) for 24 h. After incubation, the samples were removed from the medium and rinsed with deionized water to eliminate residual salts. The samples were then dried in an oven at 40 °C overnight and subsequently weighed to determine their final dry weights (W_s). The percentage of degradation was calculated as: 2.6.1. where W_i and W_s correspond to the initial and final weights of the nanofibers, respectively.

The Q loading characteristics of Zw-SiNPs, including encapsulation efficiency (EE) and loading capacity (LC), were determined by direct extraction. Briefly, 10 mg of Zw-SiNPs@Q was dispersed in 10 mL of ethanol and sonicated for 30 min to extract the loaded Q. The suspension was subsequently centrifuged at 9000 rpm for 30 min, and the supernatant was collected for analysis. The concentration of extracted Q was quantified using a UV–vis spectrophotometer (BMG Labtech CLARIOstar Plus) based on a previously established calibration curve (0–80 µg mL⁻¹). The EE and LC values were then calculated using the equations below, respectively.

EE was calculated using the following equation: 2.6.1. where W₀ is the amount of Q loaded onto the Zw-SiNPs and W₁ is the initial amount of Q used during the loading process.

LC was calculated according to the following equation: 2.6.1. where W₀ is the amount of loaded Q, and W is the total weight of quercetin-loaded nanoparticles (Zw-SiNPs@Q).

2.6.2. Biological characterization of Zw-SiNPs@Q/PVA–PAA composite nanofibers

2.6.2.1. Antibacterial activity

The antibacterial performance of PVA–PAA and Zw-SiNPs@Q/PVA–PAA NFs was evaluated against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). The tests were conducted using a plate count method based on a modified ASTM E2149 procedure, following previously reported protocols.^41,43 Bacteria were cultured overnight in nutrient broth at 37 °C and adjusted to the 0.5 McFarland standard using bacteriological peptone solution, corresponding to initial inoculum concentrations of approximately 3.0 × 10⁸ CFU mL⁻¹ for E. coli and 3.7 × 10⁷ CFU mL⁻¹ for S. aureus. The bacterial suspensions were incubated with PVA–PAA and Zw-SiNPs@Q/PVA–PAA composite NFs in tryptic soy broth at 37 °C for 24 h, while control samples were prepared under identical conditions without antibacterial agents. After incubation, serial dilutions were prepared in bacteriological peptone solution, plated onto Plate Count Agar, and incubated at 37 °C for 24 h. Viable colonies were counted, and the results were expressed as log₁₀(CFU mL⁻¹).

2.6.2.2. Antioxidant activity

Antioxidant activity was determined using the ABTS radical-scavenging assay. The ABTS˙⁺ radical was generated by mixing equal volumes of 7 mM ABTS and 2.45 mM potassium persulfate (K₂S₂O₈) solutions for 2 h, followed by incubation in the dark at room temperature for 12–16 h.⁴³ The resulting radical solution was diluted with ethanol (1 : 25) to achieve an absorbance of approximately 0.70 at 754 nm. For antioxidant activity measurements, 5 mg of PVA–PAA and Zw-SiNPs@Q/PVA–PAA composite nanofibers were mixed with 3 mL of ABTS˙⁺ solution and reacted for 6 min at room temperature. After the reaction, the mixture was centrifuged at 5000 rpm for 2 min, and the supernatant absorbance was measured at 754 nm using a UV–vis spectrophotometer.⁵⁵ The ABTS radical-scavenging activity of the composite nanofibers was calculated using the equation below. 2.6.2.2.

2.6.2.3. In vitro cytocompatibility

The in vitro cytocompatibility of the prepared nanomaterials was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay on L929 mouse fibroblast cells (ATCC® CCL-1™). Briefly, cells were seeded into a 96-well plate at an initial density of 5 × 10³ cells per well and were allowed to adhere for 24 h under standard culture conditions (37 °C, 5% CO₂). Following the attachment period, the FBS-containing culture medium was completely removed, and the test samples, including SiNPs, Zw-SiNPs, Zw-SiNPs@Q3.2, PVA–PAA NFs, and Zw-SiNPs@Q3.2/PVA–PAA NFs, were placed directly onto the cell layer. Subsequently, FBS-free DMEM was added to the wells, and the cells were incubated in direct contact with the samples for 24, 48, and 72 h. Thus, the cytocompatibility assessment was performed using a direct-contact configuration rather than an extract-based or conditioned-medium approach.⁵⁶ After the exposure period, MTT solution (5 mg mL⁻¹) was added to each well, and the plates were incubated to allow metabolically active cells to form formazan crystals. After incubation, the formazan crystals were dissolved in DMSO, and the optical density was measured at 570 nm using a microplate reader, with cells maintained solely in Dulbecco's Modified Eagle Medium (DMEM) serving as the control group. This assay enabled the quantitative evaluation of the potential cytotoxic effects of the obtained nanostructures and nanofibers on healthy fibroblast cells. 2.6.2.3.

2.6.2.4. Quantitative real-time PCR analysis

The anti-inflammatory effects of the materials were evaluated at the gene expression level using quantitative real-time PCR in L929 fibroblast cells. Cells were seeded into 12-well plates, and after 24 h of incubation, 1 µg mL⁻¹ lipopolysaccharide (LPS) (Invitrogen, USA) was added to each well to induce the inflammatory response, and the cells were incubated at 37 °C for 24 h.⁵⁷ The nanofibers were applied to stimulated cells following the previously described procedure. After 24 h at 37 °C, the medium was replaced with the NFs extract and incubated for 24 h at 37 °C. Following the experimental treatments, total RNA was isolated from the cells using a commercial RNA isolation kit (EZ-10 spin column total RNA Mini preps kit BS1361) according to the manufacturer's instructions. Complementary DNA (cDNA) was synthesized from the isolated RNA using a cDNA synthesis kit (EcoScript 5× First Strand cDNA Synthesis Kit, cat. No. ERT50). The relative mRNA expression levels of inflammatory-related genes (IL-6, IL-1β, IL-10, IL-18, IFN-γ, TGF-β, and TNF-α) were then analyzed by real-time PCR and normalized to an appropriate housekeeping gene (GAPDH).⁵⁸

2.6.2.5. In vitro scratch assay

The in vitro wound healing assay was performed using L929 fibroblast cells to evaluate the effect of the prepared materials on cell migration. Cells were seeded into 12-well plates and cultured until reaching confluence. A linear scratch was introduced using a sterile pipette tip, and detached cells were removed by gentle washing with phosphate-buffered saline. Fresh culture medium containing SiNPs, Zw-SiNPs, Zw-SiNPs@Q3.2, PVA–PAA NFs, or Zw-SiNPs@Q3.2/PVA–PAA NFs was then added, followed by incubation under standard conditions. Wound closure was monitored by acquiring images at 0, 24, 48, and 72 h with an inverted microscope and quantifying the change in wound gap distance using ImageJ software. For each image, the distance between the opposing wound edges was measured at multiple predefined points, and the mean wound width was calculated for each time point.

2.6.2.6. Statistical analysis

Each experiment was carried out three times. GraphPad Prism 9.0 software was used to perform the statistical analyses. For comparisons between two groups, an unpaired Student's t-test was used, whereas comparisons among multiple groups were performed using one-way ANOVA followed by Tukey's multiple-comparison test. Gene expression levels were compared between the control and treated groups using an unpaired Student's t-test, and statistical significance was determined based on the resulting p-values, with p < 0.05 considered statistically significant.

3. Results and discussion

Silica-based nanomaterials are widely investigated in the biomedical field due to their affordability, chemical and thermal stability, biocompatibility, and readily modifiable surface chemistry. In particular, the surface silanol groups enable the introduction of organic functional layers and the association of bioactive molecules, supporting their use as nanocarriers in drug delivery, biosensing, bioimaging, and implant-related applications.^59,60 Nonetheless, a key challenge with silica platforms is their tendency to nonspecifically bind serum proteins and promote bacterial adhesion, leading to biofilm formation, reduced function, and adverse biological effects. To overcome these issues, designing surfaces with antifouling and antibacterial properties is crucial. Especially for wound-dressing applications, bacterial colonization and subsequent biofilm formation remain important challenges that can compromise material performance and delay tissue repair. Therefore, combining silica nanocarriers with bioactive components capable of imparting antibacterial and complementary biological activities represents a relevant strategy for developing multifunctional wound-dressing systems. In the present study, SiNPs served as inorganic nanocarrier cores and were sequentially modified through zwitterionic polymer grafting and Q incorporation. The zwitterionic layer was introduced as a functional nanoengineered interface for Q association before the resulting Zw-SiNPs@Q nanocarriers were incorporated into electrospun PVA–PAA nanofibers. This hierarchical design was investigated in terms of its effects on nanoparticle characteristics, nanofiber structure, sustained Q release, and the physicochemical and biological performance of the resulting nanofibrous system. Radical graft copolymerization of DMAP onto SiNPs is initiated by the thermal decomposition of AIBN, generating reactive free radicals that extract hydrogen atoms from surface silanol groups, forming surface-bound radicals. These active sites initiate polymerization by reacting with the vinyl groups of DMAP monomers, enabling chain propagation directly from the nanoparticle surface. Polymer growth proceeds via successive monomer addition until termination occurs by radical combination or disproportionation, resulting in zwitterionic polymer chains covalently grafted onto the SiNP surface. Scheme 1 presents the proposed grafting mechanism, and the influence of monomer concentration on grafting efficiency was evaluated by FTIR analysis (see Fig. S1). Grafting yield ranged from 20.44% to 48.2%, depending on monomer and initiator concentrations. Based on the grafting yield and FTIR analysis, the initiator concentration was set to 5 wt% relative to the monomer.

3.1. Morphological, structural, and thermal characterization of Zw-SiNPs@Q

SEM (Fig. 1a–c) and TEM micrographs (Fig. 1d–f) reveal that the SiNPs exhibit a uniform spherical morphology with smooth surfaces. Upon functionalization, the overall spherical shape and dispersion remain largely preserved, confirming that the polymer coating does not induce aggregation or significant morphological distortion. The strong contrast between the nanoparticles, with a dark inner center and a relatively light edge, confirms that the DMAP copolymerizes well on the SiNPs surfaces and subsequently Q functionalization (Fig. 1e and f). Similar observations have also been reported for mesoporous silica nanoparticles grafted with a copolymer composed of 2-methacryloyloxyethyl phosphorylcholine and acryloyl-functionalized fluorescein (MSNs-co-poly(MPC–AcFl)).⁶¹

The nanoparticle dimensions, distribution, and elemental composition were examined (Fig. S2). SiNPs exhibited a narrow size distribution, with a mean particle size of 180 ± 13 nm (Fig. S2a). Following zwitterionic surface modification, Zw-SiNPs (Fig. S2b) maintained their spherical morphology, with a slight increase in particle size, resulting in an average diameter of 202 ± 16 nm, indicating successful surface grafting without significant aggregation. Upon Q functionalization, Zw-SiNPs@Q (Fig. S2c) displayed a slightly reduced mean particle size of 185 ± 15 nm, and occasional irregular or slightly lamellar-appearing structures can be attributed to the organic Q layer deposited on the Zw-SiNPs surface. This coating may partially mask the rigid spherical silica core and introduce surface heterogeneity due to uneven adsorption and drying-induced deformation during electron microscopy sample preparation. The contrast observed in TEM micrographs further supports polymer coating and subsequent Q incorporation. EDS spectra also confirm the surface modifications. SiNPs were dominated by Si (39.2 wt%) and O (47.7 wt%). After polymer grafting, the appearance of C (26.9 wt%), accompanied by a decrease in Si (28.3 wt%), indicates successful incorporation of the polymer.

Subsequent Q functionalization further increased the carbon content (56.2 wt%) and correspondingly decreased the Si content (14.5 wt%), confirming the presence of organic Q molecules on the nanoparticle surface. Morphological analyses and particle size distributions collectively confirm the stepwise surface modification of SiNPs and the formation of Zw-SiNPs@Q, consistent with similar observations reported for organic-functionalized silica-based nanostructures.^60,61

Complementary FTIR analysis (Fig. 1g) reveals characteristic Si–O–Si and Si–OH vibrations in SiNPs, along with new amide, sulfonate, and carboxylate bands in Zw-SiNPs, and additional C O and C–H stretching vibrations in Zw-SiNPs@Q, confirming sequential surface modifications. SiNPs exhibit characteristic absorption bands associated with the Si network. The strong band at 1033 cm⁻¹ corresponds to the asymmetric stretching of Si–O–Si bonds, while the band at 802 cm⁻¹ is attributed to the symmetric stretch of Si–O–Si. In addition, the presence of surface silanol groups is confirmed by the Si–OH stretch at approximately 960 cm⁻¹.^62,63 The FTIR spectrum of Zw-SiNPs exhibits several new characteristic absorption bands in addition to the retained Si-related signals. The appearance of a pronounced band at 1728 cm⁻¹ is assigned to the C O stretch of ester or carboxylate groups originating from the polymer backbone.⁶² Furthermore, the sulfonate groups (–SO₃⁻) of the zwitterionic structure are evidenced by the absorption band at 1178 cm⁻¹.⁴ The presence of quaternary ammonium groups is confirmed by the band at 1487 cm⁻¹, attributed to the bending vibrations of N⁺(CH₃)₂ moieties.⁶⁴ Weak aliphatic C–H stretching vibrations appear at around 2987 cm⁻¹, while a broad absorption band centered at approximately 3440 cm⁻¹ is associated with O–H stretching from residual hydroxyl groups and adsorbed moisture.⁶¹ These spectral features are consistent with the DMAPS-based zwitterionic polymers reported in the literature.^4,23 The FTIR spectrum of Zw-SiNPs@Q largely preserves the characteristic bands of the Zw-SiNPs, while additional absorption features corresponding to the flavonoid structure become evident. The Si–O–Si asymmetric and symmetric stretches are observed at 1095 and 821 cm⁻¹, respectively, indicating that the Si framework remains structurally intact. A distinct band at 1662 cm⁻¹ is attributed to the C O stretch of Q, while aromatic C C stretching vibrations appear at approximately 1618 cm⁻¹.^65,66 Other bands at 1516 cm⁻¹, 1213 cm⁻¹, and 3429 cm⁻¹ correspond to aromatic C–C, phenolic C–O, and O–H vibrations, respectively, confirming the presence of hydroxyl-rich Q moieties.⁶⁷

The diffraction patterns of both untreated and modified SiNPs show a broad halo at 2θ = 22.0°, which is typical of amorphous materials⁶⁸ (Fig. 1h). In addition, Zw-SiNPs and Zw-SiNPs@Q display a main broad diffraction feature at 2θ = 22.4°, attributed to the SiNPs, along with weak shoulder peaks at 2θ = 28.76° and 28.72°, respectively, associated with zwitterionic grafting.⁵¹ Additional diffraction signals observed at 2θ = 11.24°, 14.32°, and 25.44° are attributed to Q moieties.^67,69

Thermogravimetric analysis and derivative thermogravimetric (DTG/DTA) curves of SiNPs, Zw-SiNPs, and Zw-SiNPs@Q are shown in Fig. 1i. SiNPs exhibited negligible weight loss throughout the heating process, with only a minor mass decrease below 150 °C attributable to the removal of physically adsorbed water and the condensation of surface silanols, confirming the intrinsic thermal stability of the silica matrix, as widely reported for mesoporous SiNPs.⁴ Zw-SiNPs showed two weight loss stages between 250–400 °C, which were associated with the decomposition of quaternary ammonium and sulfate groups, respectively.^51,70,71 To further quantify the extent of surface functionalization, the grafting density (σ) of the zwitterionic polymer chains on the SiNPs was semi-quantitatively estimated using TGA-derived organic content in combination with particle size analysis. Based on an average particle diameter of 202 ± 16 nm and an organic mass fraction of approximately 30 wt%, the total amount of grafted polymer per particle was calculated assuming spherical geometry and a silica density of 2.0 g cm⁻³. A typical degree of polymerization (DP ≈ 50–150) for free-radical polymerization was assumed to convert monomer content into chain density. Accordingly, the grafting density was estimated to be in the range of approximately 0.3–1.0 chains per nm². This value is consistent with previously reported grafting densities for polymer brush-functionalized SiNPs estimated via similar TGA- and particle size-based approaches⁷² and within the typical range reported for surface-initiated polymer brush systems,⁷³ indicating the formation of a moderately dense zwitterionic polymer layer on the SiNPs surface. It should be noted that this estimation assumes homogeneous polymer coverage and does not provide direct information regarding the exact chain length or distribution of grafted polymers. For Zw-SiNPs@Q, three weight loss stages were observed. The first weight loss (100–200 °C) was attributed to melting, and the second and third stages (250–500 °C) were ascribed to the decomposition of the polymer chains and Q moieties.⁶⁷ Compared to Zw-SiNPs, the additional weight loss and increased organic content further confirm the incorporation of Q onto the polymer-modified Si surface.

3.2. Morphological, thermal, and structural characterization of Zw-SiNPs@Q/PVA–PAA NFs

Following the synthesis and characterization of Zw-SiNPs@Q, these nanoparticles were incorporated into PVA/PAA nanofibrous matrices via blend electrospinning. Electrospun nanofibers were selected as a structural framework to overcome the inherent limitations of nanopowders, such as poor handling, aggregation, and limited mechanical integrity, while enabling uniform nanoparticle distribution and high surface accessibility. The PVA/PAA polymer blend was chosen for its suitability for biomedical applications and water-based processability, enabling water as a green solvent during processing. In addition, the presence of hydroxyl and carboxyl groups enables post-electrospinning thermal crosslinking, thereby reducing the water solubility of the PVA/PAA nanofibrous network without the need for toxic chemical crosslinkers.^43,53

SEM micrographs of Zw-SiNPs@Q/PVA–PAA NFs containing different Zw-SiNPs@Q loadings are shown in Fig. 2a–e. All nanofiber samples exhibited homogeneous fiber distribution with smooth, continuous, and bead-free morphologies. Prior to annealing, the average fiber diameters were determined to be 96 ± 22, 94 ± 20, 91 ± 22, 85 ± 25, and 92 ± 27 nm for nanoparticle contents of 0, 0.5, 1.0, 1.6, and 3.2 wt%, respectively. The mean fiber diameters remained within a relatively narrow range across the investigated Zw-SiNPs@Q loadings, with a numerical decrease up to 1.6 wt%, which may be associated with nanoparticle-induced changes in solution conductivity and consequent variations in jet stretching during electrospinning, as previously reported for silica-containing electrospun systems.^74,75 Detailed SEM micrographs and corresponding fiber diameter distributions are provided in Fig. S3. Following thermal annealing, interconnected regions and fiber junctions were observed in both the PVA/PAA control and Zw-SiNPs@Q-containing nanofibers. This morphology is attributed to thermally induced softening and fusion of the PVA/PAA fibers under the applied annealing conditions. Due to the resulting fiber fusion and junction formation, precise measurement of post-annealing fiber diameters was not feasible.

Fig. 2f presents the TGA curves for PVA–PAA NFs and Zw-SiNPs@Q/PVA–PAA NFs, revealing multistep thermal degradation behavior. An initial minor weight loss below ∼120 °C is attributed to the removal of physically adsorbed and bound moisture, as well as volatile components, which is consistent with the hydrophilic nature of the PVA–PAA matrix and the melting-related thermal events of quercetin.^41,76 The main degradation step occurs between approximately 250 and 350 °C and is associated with the thermal decomposition of the PVA–PAA polymer chains, including backbone scission and side-group elimination. The incorporation of Zw-SiNPs@Q does not markedly shift the position of this primary degradation event, indicating that the polymer matrix retains its intrinsic thermal decomposition behavior.

The temperatures corresponding to 50% weight loss (T₅₀) were determined to be 366.42, 366.32, 369.29, 376.43, and 377.58 °C for PVA–PAA, Zw-SiNPs@Q0.5/PVA–PAA, Zw-SiNPs@Q1.0/PVA–PAA, Zw-SiNPs@Q1.6/PVA–PAA, and Zw-SiNPs@Q3.2/PVA–PAA nanofibers, respectively, indicating a gradual improvement in thermal stability with increasing Zw-SiNPs@Q content. Notably, NFs containing Zw-SiNPs@Q exhibit higher residual mass at 600 °C compared to PVA–PAA NFs. The residual weights increase from 10.59% for PVA–PAA NFs to 11.30%, 15.97%, 15.63%, and 16.04% for Zw-SiNPs@Q loadings of 0.5, 1.0, 1.6, and 3.2 wt%, respectively. This increase in char residue is attributed to the inorganic Si content and enhanced char formation promoted by Zw-SiNPs@Q. The incorporation of Zw-SiNPs@Q preserves the thermal integrity of the nanofibrous matrix while improving high-temperature residue formation.

Since PVA–PAA NFs and Zw-SiNPs@Q/PVA–PAA NFs show similar thermal behavior, the effect of the annealing process on structural properties was examined using the sample with the highest Q content. The limited change in the main degradation region, along with the increase in T₅₀ and residual mass, indicates that the nanocarriers did not alter the fundamental degradation mechanism of the polymer matrix but moderately delayed mass loss and increased the thermally stable inorganic fraction. Fig. 2g demonstrates the pre- and post-annealing FTIR spectra of both PVA–PAA NFs and Zw-SiNPs@Q3.2/PVA–PAA NFs. In the pre-annealed PVA–PAA NFs, the broad absorption band centered at ∼3327–3337 cm⁻¹ is assigned to O–H stretching vibrations from hydroxyl groups in PVA and carboxylic acid groups in PAA, as well as absorbed moisture. The bands at ∼2950–2945 cm⁻¹ correspond to C–H stretching vibrations of the polymer backbone. A strong carbonyl stretching band observed at ∼1715–1717 cm⁻¹ is characteristic of the C O groups of PAA.⁴¹ Upon annealing, the carbonyl band shifts slightly to lower wavenumbers (∼1709 cm⁻¹ for PVA–PAA and ∼1719 cm⁻¹ for Zw-SiNPs@Q3.2/PVA–PAA nanofibers), indicating the formation of intermolecular ester linkages between PVA hydroxyl groups and PAA carboxyl groups. This shift, together with the reduced intensity and narrowing of the O–H stretching band, provides clear evidence of thermal crosslinking within the nanofibrous matrix. For Zw-SiNPs@Q3.2/PVA–PAA nanofibers, additional absorption bands at ∼1443 and ∼1173 cm⁻¹ are observed, which can be attributed to aromatic C–C stretching and C–O vibrations associated with Q moieties.⁶⁷ These bands persist after annealing, indicating that Q remains structurally intact during thermal treatment and is partially retained within the crosslinked nanofiber network.

Fig. 3a illustrates the swelling ratios of the annealed PVA–PAA NFs and Zw-SiNPs@Q/PVA–PAA NFs with different Zw-SiNPs@Q loadings as a function of immersion time. All samples exhibit rapid initial swelling within the first few hours, followed by a more gradual increase and eventual stabilization, indicating diffusion-controlled water uptake and network relaxation. PVA–PAA NFs show relatively moderate and stable swelling ratios over time, reflecting the formation of a crosslinked polymer network. In contrast, Zw-SiNPs@Q-containing NFs display higher swelling ratios, which increase with Zw-SiNPs@Q content up to 1.6 wt%. This enhanced swelling can be attributed to the hydrophilic zwitterionic groups and Q moieties, which promote water absorption through hydrogen bonding and ionic interactions. The Zw-SiNPs@Q1.6/PVA–PAA NFs exhibit the highest swelling ratio, reaching a maximum at 48 h, suggesting an optimal balance between hydrophilicity and network integrity. At the highest nanoparticle loading (3.2 wt%), the swelling ratio decreases compared to the 1.6 wt% sample, likely due to increased physical crosslinking and restricted polymer chain mobility arising from higher nanoparticle content and inter-fiber junction formation. After prolonged immersion (72–96 h), all samples show a slight reduction or stabilization in swelling ratio, which reflects partial network relaxation or minor structural rearrangements within the nanofibrous matrix. These results demonstrate that the swelling behavior of PVA–PAA NFs can be effectively tuned by adjusting the Zw-SiNPs@Q content.

Fig. 3b presents the hydrolytic degradation behavior of annealed Zw-SiNPs@Q/PVA–PAA NFs. The incorporation of Zw-SiNPs@Q nanoparticles results in a pronounced, nearly uniform reduction in degradation, with a maximum decrease of approximately 56.5% compared to the PVA–PAA nanofibers. The reduced mass loss indicates improved hydrolytic stability of the Zw-SiNPs@Q-containing nanofibers compared with the PVA–PAA control. This behavior may arise from interactions between the incorporated nanocarriers and the polymer network that restrict polymer chain mobility and water-induced matrix disruption.^44,77 Notably, a similar improvement in the water stability of PVA/PAA nanofibers was observed in our previous study upon incorporation of mBN.⁴¹

The encapsulation efficiency (EE) and loading capacity (LC) of Q within the Zw-SiNPs were determined to be 20.4 ± 4.6% and 39.5 ± 8.4%, respectively. Fig. 3c presents the cumulative Q release profiles of PVA–PAA nanofibers containing different concentrations of Zw-SiNPs@Q in PBS (pH 7.4) at 37 °C. PVA–PAA nanofibers showed no absorbance at 375 nm, confirming the absence of Q and no interference from the polymer matrix.

Zw-SiNPs@Q/PVA–PAA nanofibers exhibited a time-dependent release profile characterized by an initial release during the first 12 h, followed by a more gradual and sustained release up to 72 h. The absence of a pronounced burst release suggests that Q was effectively immobilized within the Zw-SiNPs and further retained by the PVA–PAA nanofibrous network, rather than being simply adsorbed on the fiber surface. The cumulative amount of released Q increased with increasing Zw-SiNPs@Q content. After 72 h, the cumulative release reached approximately 172.5 ± 23.6, 322.0 ± 9.1, 395.6 ± 67.9, and 865.6 ± 50.4 µg for Zw-SiNPs@Q0.5/PVA–PAA, Zw-SiNPs@Q1.0/PVA–PAA, Zw-SiNPs@Q1.6/PVA–PAA, and Zw-SiNPs@Q3.2/PVA–PAA nanofibers, respectively. The Zw-SiNPs@Q3.2 formulation released nearly five times more Q than the Zw-SiNPs@Q0.5 formulation, showing that higher loading increases the amount of Q stored in the nanofibers.

The gradual release behavior can be attributed to the combined effects of Q diffusion from the Zw-SiNPs, its interactions with the Zw functional groups, and the diffusion barrier provided by the PVA–PAA matrix. Hydrogen bonding between Q and the hydroxyl and carboxyl groups of the polymer network, along with electrostatic interactions within the zwitterionic coating, likely retarded Q diffusion into the surrounding medium, resulting in sustained release over 72 h.

The release profile demonstrates that the Zw-SiNPs@Q/PVA–PAA nanofibers provide a controllable, concentration-dependent delivery platform that maintains prolonged Q release under physiological conditions. Such sustained-release behavior is particularly advantageous for wound-dressing applications, where continuous local delivery of antioxidant and anti-inflammatory agents can reduce the need for frequent dressing changes while maintaining therapeutic activity. From this perspective, a sustained and controlled Q release profile has been shown to be critical for preventing secondary tissue trauma during dressing changes and for modulating the chronic inflammatory microenvironment to minimize scar formation.⁷⁸

Fig. 3d shows pre- and post-annealing antioxidant activities of Zw-SiNPs@Q/PVA–PAA NFs as a function of Zw-SiNPs@Qcontent. Before annealing, NFs containing ≥0.5% (w/w) Zw-SiNPs@Q exhibit very high antioxidant activity (RSA% ≈95–100%), indicating the effective radical-scavenging activity of the incorporated Zw-SiNPs@Q. After annealing, a content-dependent reduction in antioxidant activity is observed at lower Zw-SiNPs@Q loadings (0.5–0.8%), whereas at higher loadings (≥1.0%), the activity remains comparable to that of the pre-annealed samples. This behavior may be associated with annealing-induced interpolymer crosslinking, matrix densification, and partial encapsulation of Zw-SiNPs@Q within the PVA–PAA network, which could reduce the accessibility of antioxidant sites at lower nanoparticle loadings. At higher Zw-SiNPs@Q contents, sufficient antioxidant activity was retained after annealing, suggesting that the greater amount of incorporated Zw-SiNPs@Q compensated for the reduced accessibility caused by matrix densification.

Before annealing, Zw-SiNPs@Q0.5/PVA–PAA nanofibers exhibited very high antioxidant activity (RSA = 99.04 ± 0.34%). To determine whether a comparable maximal antioxidant effect could be achieved by increasing the amount of NF, antioxidant activity was evaluated using different amounts of Zw-SiNPs@Q/PVA–PAA nanofibers. As shown in Fig. 3e, the pre-annealed NFs reached near-quantitative radical scavenging activity at relatively low amounts, whereas post-annealed samples required substantially higher NF amounts to approach similar antioxidant performance. This result indicates that annealing reduces the immediate accessibility of Q-based antioxidant sites, making the overall scavenging efficiency more dependent on the quantity of NF. Nevertheless, at sufficiently high nanofiber loadings (≥25 mg), post-annealed samples exhibited antioxidant activity comparable to that of pre-annealed nanofibers, confirming that the intrinsic antioxidant capacity is preserved despite annealing-induced structural densification.

Fig. 4a qualitatively demonstrates the antibacterial performance of Zw-SiNPs@Q/PVA–PAA NFs against E. coli (Gram-negative) and S. aureus (Gram-positive) under pre- and post-annealing conditions. Pre-annealed NFs exhibit complete inhibition of bacterial growth for both strains, indicating 100% antibacterial activity, as evidenced by the absence of visible colonies. In contrast, post-annealed nanofibers retain antibacterial activity primarily at higher Zw-SiNPs@Q loadings, with a pronounced effect against S. aureus. The quantitative results in Fig. 4b corroborate these observations, showing a substantial reduction in colony-forming units (CFU mL⁻¹) in pre-annealed samples, whereas post-annealed samples exhibit concentration-dependent antibacterial efficacy, particularly against S. aureus. The reduced antibacterial activity against E. coli after annealing is likely attributable not only to the intrinsic outer membrane barrier of Gram-negative bacteria, which limits interaction with antibacterial agents, but also to annealing-induced structural changes in the nanofibrous matrix. In contrast, Gram-positive S. aureus, lacking this outer membrane, remains more susceptible to surface-associated antibacterial effects.⁷⁹ Additionally, the tendency of S. aureus to form cellular aggregates may affect its interaction with the nanofibrous matrix, further contributing to the observed antibacterial response.⁸⁰ Taken together, these findings indicate a trade-off between the structural stabilization achieved by thermal annealing and the accessibility of the bioactive components. Thermal crosslinking improved the aqueous integrity of the PVA–PAA matrix but likely restricted the diffusion and surface availability of Q and nanocarrier-associated active sites, particularly at lower Zw-SiNPs@Q loadings. The recovery of stronger antibacterial activity at higher nanocarrier contents suggests that reduced accessibility caused by matrix densification can be partially compensated for by increasing Zw-SiNPs@Q loading. Therefore, both the annealing conditions and nanocarrier concentration are critical parameters for balancing scaffold stability and antibacterial performance.

Compared to our previous work on mBN-reinforced PVA/PAA nanofibers, which achieved bacterial reduction efficiencies of 65% for E. coli and 75% for S. aureus, the present Zw-SiNPs@Q system—particularly in the pre-annealed state—demonstrates enhanced antibacterial performance, highlighting the role of nanoparticle chemistry and post-processing conditions in governing antibacterial activity.⁴¹ This comparison indicates that the chemical nature and bioactive functionality of the incorporated nanocarriers, together with the applied post-processing conditions, play important roles in determining the antibacterial performance of PVA–PAA-based nanofibrous systems.

Based on antibacterial performance, PVA–PAA NFs containing the highest Zw-SiNPs@Q content were selected for further biological evaluation. Fig. 5 shows biocompatibility, anti-inflammatory activity, and wound-healing performance. Cell viability was assessed after exposure to SiNPs, Zw-SiNPs, Zw-SiNPs@Q3.2, PVA–PAA NFs, and Zw-SiNPs@Q3.2/PVA–PAA NFs using a colorimetric viability assay (Fig. 5a). Following 24 h of cell attachment, the fiber samples were placed directly onto the L929 cells and maintained in contact with the cells for 24, 48, or 72 h before the corresponding MTT measurements. Untreated L929 cells served as the control group. The results are presented as mean ± standard deviation, and cell viability was expressed as a percentage relative to the control. Statistical analyses were performed to evaluate differences between the treatment groups and the untreated control, with statistically significant differences indicated by the corresponding p-values. The viability of all tested materials remained above 80% across the evaluated exposure periods, indicating that the tested materials did not cause substantial cytotoxicity in L929 fibroblasts. Moreover, the maintenance of cell viability above 80% over 24, 48, and 72 h suggests that the tested materials exhibited good cytocompatibility without a pronounced time-dependent cytotoxic effect. These findings support the suitability of SiNPs, Zw-SiNPs, Zw-SiNPs@Q3.2, PVA–PAA NFs, and Zw-SiNPs@Q3.2/PVA–PAA NFs for further biological and wound-healing evaluations.

With their safety profile confirmed, the investigation was extended to evaluate their immunomodulatory effects in an LPS-induced inflammatory model. Fig. 5b clearly demonstrates that incorporation of Zw-SiNPs@Q3.2 into PVA–PAA NFs significantly altered cytokine expression compared to PVA–PAA NFs. While the PVA–PAA NFs exhibited expression levels near baseline, the Zw-SiNPs@Q3.2/PVA–PAA NFs markedly downregulated key pro-inflammatory cytokines, including IL-6, TNF-α, and IFN-γ. The pronounced reduction in TNF-α and IL-6 indicates effective attenuation of the LPS-triggered inflammatory response.

In contrast, anti-inflammatory and regenerative mediators such as IL-10 and TGF-β were significantly upregulated in the Zw-SiNPs@Q3.2-containing group, suggesting activation of pathways associated with the resolution of inflammation and tissue repair. The substantial increase in TGF-β further supports enhanced remodeling and wound-healing potential. Interestingly, IL-18 expression was also elevated, which may reflect a controlled immune activation linked to early repair signaling rather than excessive inflammation.⁸¹

The observed cytokine profile, characterized by decreased expression of IL-6, TNF-α, and IFN-γ together with increased levels of IL-10 and TGF-β, suggests a shift toward a pro-resolving and tissue-repair-oriented microenvironment. The upregulation of IL-10 and TGF-β is consistent with inflammation resolution and remodeling processes. Although IL-18 and IL-1β were elevated, this increase may reflect a controlled early inflammatory activation required for effective wound healing rather than sustained or excessive inflammation. These findings indicate a balanced immunomodulatory response rather than complete inflammatory suppression.

Although a Q-only control was not included, comparison with PVA–PAA and Zw-SiNPs systems suggests that the enhanced activity arises from the combined presence of Q and Zw-SiNPs. This enhanced anti-inflammatory effect can plausibly be attributed to the controlled and localized release of Q from the Zw-SiNPs@Q3.2/PVA–PAA NFs. Is a carbohydrate-free flavonoid with potent antioxidant and anti-inflammatory activity, known to suppress NF-κB signaling and oxidative stress, thereby reducing pro-inflammatory cytokine overproduction and modulating immune responses.^81–83 Additionally, the nanofibrous matrix likely facilitates sustained release and improved cell–material interactions, further strengthening the overall immunomodulatory response.

Fig. 5c presents the quantitative analysis of wound gap closure over 0–72 h in L929 cells treated with PVA–PAA NFs and Zw-SiNPs@Q3.2/PVA–PAA NFs compared to the untreated control. Although the control and PVA–PAA groups show only gradual wound closure, incorporation of Zw-SiNPs@Q3.2 markedly accelerates gap reduction, particularly at 48 and 72 h. By 72 h, the wound gap was reduced to approximately 30% in the Zw-SiNPs@Q3.2/PVA–PAA NFs group, whereas the control and PVA–PAA groups remained around 60%, indicating significantly enhanced fibroblast migration and wound-healing activity. The representative scratch images in Fig. 5d visually corroborate these quantitative results, showing more rapid closure of the scratched region and increased cellular infiltration into the wound area in the Zw-SiNPs@Q3.2/PVA–PAA NFs group. In contrast, wider gaps persist in the control and PVA–PAA NFs at later time points. Importantly, these findings are consistent with the observed cytokine profile, which demonstrated suppression of excessive pro-inflammatory mediators (IL-6, TNF-α, IFN-γ) alongside upregulation of pro-repair cytokines such as IL-10 and TGF-β.

The effects of PVA–PAA NFs and Zw-SiNPs@Q3.2/PVA–PAA NFs on the expression of inflammation-related genes were further evaluated in L929 fibroblasts (Fig. 5b). Compared with the PVA–PAA NF group, Zw-SiNPs@Q3.2/PVA–PAA NFs significantly modulated the expression of several inflammatory mediators. The expression levels of IL-6, IFN-γ, and TNF-α were significantly reduced, whereas TGF-β, IL-18, IL-10, and IL-1β showed significant increases. The reduction in IL-6 and TNF-α expression suggests attenuation of major pro-inflammatory signaling pathways, while the increased IL-10 expression may indicate activation of an inflammation-resolving response. These findings therefore suggest that Zw-SiNPs@Q3.2/PVA–PAA NFs modulate, rather than simply suppress, inflammatory gene expression in L929 fibroblasts. Such differential regulation may contribute to the cellular response associated with the wound-healing process. Similar differential regulation of wound-healing mediators has been reported for biomaterial-based wound dressings. Nunes et al. demonstrated that a PVA-based biomembrane modulated both pro- and anti-inflammatory mediators, including TGF-β, IL-10, IL-6, IL-1β, and TNF-α, in L929 fibroblasts.⁸⁴ Hagh Ranjbar and Hosseini Abari reported that ECT/ε-PL/PVA electrospun fibers promoted L929 fibroblast migration and increased TGF-β expression while reducing TNF-α expression, supporting the role of differential inflammatory and repair-related gene regulation in fiber-mediated wound healing.⁸⁵ In the present study, the simultaneous changes in TGF-β, IL-6, TNF-α, and other inflammatory mediators similarly suggest that Zw-SiNPs@Q3.2/PVA–PAA NFs may modulate the wound-healing microenvironment rather than uniformly suppress inflammatory signaling.

Recent studies have shown that quercetin can significantly accelerate wound closure in both in vitro and in vivo models by modulating inflammatory pathways and enhancing cellular responses critical for tissue repair.^82,86 For example, quercetin has been reported to promote cutaneous wound closure and reduce inflammatory burden in animal models, with quercetin treatment leading to faster re-epithelialization and higher rates of wound contraction than untreated controls, associated with reduced pro-inflammatory cytokines and improved regenerative signaling.⁸⁷ Beyond its anti-inflammatory effects, quercetin's antioxidant properties and regulation of redox–sensitive pathways contribute to a microenvironment favorable for fibroblast proliferation and extracellular matrix deposition. The incorporation of Zw-SiNPs@Q3.2 into the PVA–PAA NFs appears to promote a pro-resolving, regenerative environment that supports fibroblast migration and tissue repair.

Taken together, the multifunctional biological performance of the developed system suggests the involvement of multiple interacting mechanisms. The observed biological effects likely arise from multiple contributions: (i) Q-mediated antioxidant and anti-inflammatory activity, (ii) zwitterionic surface-induced modulation of protein adsorption and bacterial adhesion, and (iii) structural effects of the nanofibrous matrix, including changes in fiber morphology and accessibility after annealing. While Q clearly plays a central role, the overall biological response cannot be attributed to a single component.

Conclusion

In this study, a hierarchical nanofibrous platform was developed by grafting zwitterionic polymer chains onto silica nanoparticles, immobilizing quercetin (Q) on the modified nanoparticles, and incorporating the resulting Zw-SiNPs@Q nanocarriers into thermally crosslinked PVA–PAA electrospun nanofibers. Zwitterionic grafting yields ranging from 20.44 to 48.2% were obtained, while the mean particle diameter changed from 180 ± 13 nm for SiNPs to 202 ± 16 nm after zwitterionic modification and 185 ± 15 nm after Q functionalization. The resulting nanofibers exhibited continuous, bead-free morphologies, with mean fiber diameters ranging from 85 ± 25 to 96 ± 22 nm across the investigated formulations.

Incorporation of Zw-SiNPs@Q improved the physicochemical and functional performance of the PVA–PAA nanofibrous matrix. At a Zw-SiNPs@Q content of 3.2 wt%, the temperature corresponding to 50% mass loss increased from 366.42 to 377.58 °C, while the residual mass at 600 °C increased from 10.59 to 16.04%. The incorporated nanocarriers also reduced hydrolytic degradation by up to approximately 56.5% relative to the PVA–PAA control. Zw-SiNPs exhibited a Q encapsulation efficiency of 20.4 ± 4.6% and a loading capacity of 39.5 ± 8.4%. Importantly, the Zw-SiNPs@Q/PVA–PAA nanofibers provided sustained and concentration-dependent Q release for up to 72 h without a pronounced burst effect; the cumulative release increased from 172.5 ± 23.6 µg for Zw-SiNPs@Q0.5/PVA–PAA to 865.6 ± 50.4 µg for Zw-SiNPs@Q3.2/PVA–PAA, corresponding to an approximately 5-fold increase. The developed nanofibers also showed multifunctional biological activity. Before annealing, Zw-SiNPs@Q0.5/PVA–PAA nanofibers achieved an ABTS radical-scavenging activity of 99.04 ± 0.34%, and the pre-annealed formulations completely inhibited both E. coli and S. aureus. After annealing, antioxidant and antibacterial activities became dependent on nanocarrier content, demonstrating that thermal crosslinking influenced the accessibility of the bioactive components. Nevertheless, all tested materials maintained L929 fibroblast viability above 80% for up to 72 h. Zw-SiNPs@Q3.2/PVA–PAA nanofibers also attenuated LPS-induced inflammatory responses by suppressing IL-6, TNF-α, and IFN-γ expression while enhancing IL-10 and TGF-β levels. This immunomodulatory response was accompanied by enhanced fibroblast migration and accelerated wound gap closure in vitro. In the scratch assay, the residual wound gap decreased to approximately 30% after 72 h, compared with approximately 60% for control groups.

The hierarchical integration of a Zw nanoengineered interface, sustained Q delivery, and a crosslinked nanofibrous framework provides a multifunctional platform combining antioxidant, antibacterial, immunomodulatory, and wound-healing properties. The presented strategy demonstrates the potential of nano-biointerface engineering to integrate multiple complementary functions within a single nanofibrous system for advanced wound management and tissue repair applications.

Conflicts of interest

There are no conflicts to declare.

Supplementary Material

NA-OLF-D6NA00563B-s001

NA-OLF-D6NA00563B-s001.pdf^{(1.7MB, pdf)}

Acknowledgments

This work was supported by the Scientific Research Projects Coordination Unit of Kırıkkale University (Project No. 2024/107). Graphical abstract was created with the assistance of Google Gemini.

Data availability

The data supporting this study are available in the following google drive repository: [https://drive.google.com/drive/folders/1CUtIp-MQH9uvTr7mg-apjLyvgbnig-zU?usp=sharing]. The datasets generated and analysed during the current study include characterization data (SEM, TEM, FTIR, XRD, and TGA), quercetin release profiles, antibacterial assay results, antioxidant activity data, cytokine profiling data, cytocompatibility analyses, and wound-healing assay results. Processed data used to generate the figures were analysed using OriginPro 2026 (FTIR, XRD, TGA, quercetin release, antibacterial and antioxidant assays) and GraphPad Prism 9.0 (cytokine profiling, cytocompatibility, and wound-healing). For the in vitro wound healing assay, wound areas were quantified using Fiji (ImageJ, National Institutes of Health, Bethesda, MD, USA), and the percentage of wound closure was calculated relative to the initial wound area. Gene expression analysis was performed using PikoReal Software version 2.2 (Thermo Fisher Scientific, Finland), and relative mRNA expression levels were calculated using the 2^−ΔΔCt method after normalization to the housekeeping gene.

Supplementary information (SI): FTIR spectra illustrating the influence of monomer concentration on grafting efficiency, SEM micrographs, EDS spectra, and particle size distribution plots of the nanoparticles, as well as SEM micrographs and fiber diameter distribution plots of the electrospun nanofibers. See DOI: https://doi.org/10.1039/d6na00563b.

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Supplementary Materials

NA-OLF-D6NA00563B-s001

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Data Availability Statement

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PERMALINK

Silica meets flavonoid: zwitterionic silica–quercetin nanocarriers embedded in electrospun fibers for wound healing

Nesrin Horzum

Fatma Rabia Karaduman

Sena Nur Köksal

Aslı Eldem

Özlem Karakoç

Ayşegül Ülkü Metin

Abstract

1. Introduction

2. Materials and methods

2.1. Materials

2.2. Synthesis of silica nanoparticles

2.3. Grafting of zwitterionic polymer on SiNPs

2.4. Functionalization of zwitterionic polymer-coated SiNPs with Q

2.5. Engineering PVA–PAA nanofibers reinforced with bioactive Zw-SiNPs@Q

2.6. Characterization

2.6.1. Morphological and structural characterization Zw-SiNPs@Q nanoparticles and Zw-SiNPs@Q/PVA–PAA composite nanofibers

2.6.2. Biological characterization of Zw-SiNPs@Q/PVA–PAA composite nanofibers

2.6.2.1. Antibacterial activity

2.6.2.2. Antioxidant activity

2.6.2.3. In vitro cytocompatibility

2.6.2.4. Quantitative real-time PCR analysis

2.6.2.5. In vitro scratch assay

2.6.2.6. Statistical analysis

3. Results and discussion

Scheme 1. Proposed graft polymerization route of DMAP on SiNPs.

3.1. Morphological, structural, and thermal characterization of Zw-SiNPs@Q

Fig. 1. SEM and TEM micrographs of SiNPs (a and d), Zw-SiNPs (b and e), Zw-SiNPs@Q (c and f), along with FTIR spectra (g), XRD patterns (h), and TGA/DTG curves (i) of the synthesized nanomaterials.

3.2. Morphological, thermal, and structural characterization of Zw-SiNPs@Q/PVA–PAA NFs

Fig. 2. SEM micrographs of Zw-SiNPs@Q/PVA–PAA NFs containing different amounts of Zw-SiNPs@Q (% w/w): 0 (a), 0.5 (b), 1.0 (c), 1.6 (d), and 3.2 (e). Subscripts ‘i’ and ‘ii’ denote pre- and post-annealing, respectively. TGA curves (f) and FTIR spectra (g) of the NFs.

Fig. 3. Swelling ratio (a), degradation percentage (b), release profile of Q (c) from the post-annealed Zw-SiNPs@Q/PVA–PAA NFs, antioxidant activity of Zw-SiNPs@Q/PVA–PAA NFs (5 mg) with varying Zw-SiNPs@Q contents (d), and of different amounts of NFs containing Zw-SiNPs@Q0.5 (e).

Conclusion

Conflicts of interest

Supplementary Material

Acknowledgments

Data availability

References

Associated Data

Supplementary Materials

Data Availability Statement

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