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. 2025 Oct 1;31:103116. doi: 10.1016/j.fochx.2025.103116

Interaction between hyaluronic acid and phospholipid bilayer and its influence on stability and bioavailability of luteolin-loaded liposomes

Le Cheng a, Ming Zhang b, Lin Dong a, Yifei Wang a, Jianguo Dong a, Fang Wu a, Chenyan Zheng a, Yumeng Ma a, Zihan Wang a, Ran Wang a, Yixuan Li a, Bing Fang a,⁎
PMCID: PMC12524136  PMID: 41103388

Abstract

The poor solubility of luteolin limits its food applications, and while liposomes offer a potential delivery solution, their phospholipid bilayer membranes are unstable. To overcome these dual challenges, this study developed hyaluronic acid (HA)-coated luteolin liposomes (HA-LUT-lips). HA-LUT-lips exhibited a core-shell structure, high encapsulation efficiency, and good dispersibility. Fourier transform infrared spectroscopy (FTIR) confirmed HA interacted with liposomes via hydrogen bonds, while Raman spectroscopy (RS) showed HA reduced membrane fluidity and enhanced lipid lateral packing. Thermogravimetric (TG) analysis and differential scanning calorimetry (DSC) revealed that HA-LUT-lips were more thermally stable than LUT-lips. HA coating also enhanced ionic strength and storage stability, slowing luteolin release during simulated digestion. HA coating can resist the oxidation of liposomes and delay the leakage of luteolin. These findings suggest HA-coated liposomes were a promising delivery system for luteolin in functional foods and nutritional enhancers.

Keywords: Liposomes, Luteolin, Hyaluronic acid, Interactions, Stability, Oxidation

Graphical abstract

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Highlights

  • •

    Hyaluronic acid (HA) modified luteolin (LUT) liposomes had a core-shell structure.

  • •

    HA interacted with LUT-lips through hydrogen bonding.

  • •

    HA-LUT-lips enhanced the thermal and environmental stability.

  • •

    HA-LUT-lips exhibited a sustained release of LUT in vitro digestion.

  • •

    HA coating resisted the liposomes oxidation and delayed the leakage of LUT.

1. Introduction

Luteolin (LUT) is a 3′, 4′, 5′, 7′-tetrahydroxy flavone with a C6-C3-C6 skeleton structure, widely discovered in plants and fruits such as perilla leaves, celery, apples, oranges, and green peppers (Ren, Cao, et al., 2024). Luteolin is used in medications and functional foods due to its various biological activities, including antioxidant (Aruwa et al., 2021), anti-inflammatory (Chen et al., 2023; Sun, Sun, et al., 2025), antibacterial (Mahamud et al., 2024), anticancer (Rauf et al., 2024), and antiviral (Zhang et al., 2020). However, luteolin is unstable and prone to loss of activity due to heat and oxidation. Its low solubility and bioavailability further limit its practical application in the food industry (Gao et al., 2024). Encapsulating LUT in liposomes was an effective measure to improve its solubility and bioavailability (Li et al., 2022).

Liposomes are spherical vesicles made of hydrophilic cores and hydrophobic phospholipid bilayers that are self-assembled when polar phospholipids are scattered in aqueous solutions. Liposomes can simultaneously deliver hydrophilic and hydrophobic materials with high encapsulation efficiency, biocompatibility, targeting ability, and sustained release potential (Cheng, Ji, et al., 2024). Previous studies have confirmed that encapsulating luteolin in liposomes improved its bioavailability (Zhang et al., 2020). However, liposomes themselves are physically and chemically unstable because of their weak lipid bilayer structure. They may be sensitive to external elements including heat, osmotic pressure, oxygen, and the gastrointestinal tract, which can weaken liposomes and enable encapsulated substances to leak out (Singh et al., 2024). Therefore, the development of an efficient structural modification method is urgently needed to increase the mechanical stability of liposomes and improve their functional performance in a variety of storage and digestive conditions.

The modification of biopolymers on the liposomes' surface is proposed to be an advantageous strategy to improve the structural stability and delivery ability of liposomes (Huang, Lu, et al., 2024). Biopolymers adhere to the liposome surface via interactions such as hydrogen bonding and coordination bonds, forming nanoliposomes with a core-shell structure (Tan et al., 2021). The desorption and incorporation of biopolymers affect the shape and size of liposomes. Through rational design, the surface function of vesicle is adjusted, then improving storage stability (Wu et al., 2023). HA is favored due to its low cost and availability as a natural ingredient and is approved as a novel food by USA, European Union, China, and other countries. HA is a hydrophilic polysaccharide made up of repeated disaccharide units of N-D-glucuronic acid and N-acetylglucosamine connected alternatively by β-1,4-glycosidic and β-1,3-glycosidic linkages (Ye et al., 2023). HA has great biodegradability and good biocompatibility, which may be used to improve the delivery of insoluble luteolin. In addition, HA can also prevent the leaking of the encapsulated substances and improve delivery efficiency. While HA has been explored as a coating material for various nanocarriers, its specific role as a structural regulator for liposomes, particularly in modulating the physicochemical properties and stability of the phospholipid bilayer, remains underexplored (Li et al., 2025). This gap highlights the need for a systematic investigation into the HA-liposome interaction to facilitate the rational design of delivery systems.

Therefore, this study analyzed the interaction mechanism between HA and phospholipid bilayers, and how this interaction enhanced the functional performance of LUT liposomes. HA-LUT-lips were prepared and the physicochemical parameters of their liposomes were examined, including size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE) and loading capacity (LC). The morphology of liposomes was analyzed using TEM and AFM. The interaction between HA and phospholipid bilayers in liposomes was analyzed using Fourier transform spectroscopy and Raman spectroscopy, and the crystallinity of LUT in liposomes was determined with or without the addition of HA. Thermal stability was determined using a thermogravimetric analyzer (TG) and a differential scanning calorimeter (DSC). Further evaluation was conducted on the environmental stability (ion strength and storage temperature) and in vitro simulated digestion performance of HA-LUT-lips. Finally, the inhibitory effect of HA-LUT- lips on lipid oxidation was analyzed. In this study, the HA-modified liposomes provided a potential method for designing novel nano-delivery systems for nutritional supplements.

2. Material and methods

2.1. Materials

Lecithin from egg yolk (>95 % purity) and Tween 80 were obtained from Sangon Biotech Co., Ltd., Shanghai, China. Cholesterol (>98 % purity) and luteolin (97.2 % purity) were purchased from Shanghai Yuanye Biotechnology Co. Ltd., Shanghai, China. Hyaluronic acid (>97 % purity) was sourced from Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai, China. Mucin from porcine stomach, pepsin from porcine gastric mucosa (enzymatic activity ≥ 400 units/mg protein), pancreatin from porcine pancreas (4 × USP) and bile salts (>96 % purity) were purchased from Merck (Shanghai, China). All reagents were of analytical grade.

2.2. Preparation of liposomes, LUT-lips and HA-LUT-lips

Liposomes were prepared using a thin-film hydration assisted with an ultrasonic treatment method (Liu et al., 2024). Lecithin (1.2 g), cholesterol (0.12 g), and Tween 80 (0.3 g) were dissolved in 60 mL of ethanol. The combined solution was sent to a rotary evaporator (RE-52AA, Shanghai Yarong, China). At 40 °C, the solvent was evaporated until a homogeneous layer developed. Following that, 120 mL of PBS was used to hydrate the dry lipid membrane. Lecithin's final mass concentration in PBS was 10 mg/mL. Under ice bath conditions, ultrasound treatment was performed for 15 min (50 Hz, work 1 s, stop 1 s) using an ultrasonic cell disruptor (VCX 400, Sonic, USA) to produce liposomes with a final lecithin concentration of 10 mg/mL, cholesterol concentration of 1 mg/mL, and Tween 80 concentration of 2.5 mg/mL. Liposomes were lyophilized by subjecting them to 0.005 MPa (−40 °C) for 36 h in a freeze dryer (LGJ-10, Beijing Songyuanhuaxing Technology Develop Co., Ltd., China). Before usage, the lyophilized material was dissolved in phosphate buffered saline (PBS) to produce a 1 mg/mL liposome suspension. LUT-lips were made by dissolving 0.12 g of luteolin, 1.2 g of lecithin, 0.12 g of cholesterol, and 0.3 g of Tween 80 in 60 mL of ethanol. The next procedure was similar to the preparation method of liposomes and the obtained LUT-lips with a final lecithin concentration of 10 mg/mL, luteolin 1 mg/mL, cholesterol 1 mg/mL, and Tween 80 at 2.5 mg/mL. Hyaluronic acid (HA) was dissolved in PBS to achieve 0.25, 0.5, 0.75, and 1.0 mg/mL. To prepare HA-LUT-lips, different concentrations of HA were added at a rate of 30 drops/min to an equal volume of LUT-lips solution (1 mg/mL) at 800 r/min for 2 h using a magnetic stirrer (C-MAG HS10, IKA Works, USA).

2.3. Particle size, polydispersity index (PDI), and zeta-potential

The Malvern Laser Particle Size Analyzer (Nano-ZS, Malvern, UK) was used to measure the sample's average particle size, PDI, and zeta potential at a scattering angle of 90° at 25 °C. The sample was diluted 100-fold with PBS before taking the test.

2.4. Encapsulation efficiency (EE) and loading capacity (LC)

The supernatant from 5 mL aliquots of liposome samples was collected by centrifugation at 10000 r/min for 40 min at 4 °C. The supernatant was measured the amount of unencapsulated luteolin by a UV/Vis spectrophotometer at 374 nm. The standard curve of luteolin was used to quantify the mass of unencapsulated luteolin. The EE and LC of the LUT was determined using the following formulae:

EE%=Total amount ofLUT−Free amount ofLUTTotal amount ofLUT×100% (1)
LC%=The amount ofLUTThe amount of liposome×100% (2)

2.5. Morphology observation

2.5.1. Transmission electron microscopy (TEM)

A transmission electron microscope (H-7650, Hitachi Ltd., Tokyo, Japan) equipped with a 100 kV acceleration voltage was used to assess the morphology of the liposome sample.

2.5.2. Atomic force microscopy (AFM)

The microstructure of liposome sample was observed using an AFM (Dimension Icon, Bruker, Germany). The scanning rate was 1 Hz, dimensions was 5 μm × 5 μm, and resolution was 512 × 512 pixels.

2.6. Fourier transform infrared spectroscopy (FTIR) analysis

Based on Wang, Yu, et al. (2025), The FTIR spectra of liposome samples were recorded using a FTIR spectrophotometer (Nicolet iS20, Thermo Fisher, USA) in the range of 4000 to 400 cm−1. Freeze-dried liposomes and KBr were ground into powder and compressed into semi-transparent sheets for analysis using the potassium bromide disk method. All spectra were averaged across 64 scans, with a spectral resolution of 4 cm−1.

2.7. Raman spectra (RS) analysis

RS of liposome samples were measured by a Raman spectrometer (Horiba Jobin Yvon, HIROBA, France) at 25 °C with a laser wavelength of 785 nm.

2.8. X-ray diffraction (XRD) analysis

The crystal structure of liposomes was investigated using an X-ray diffractometer (Bruker D8 advance, Germany). Before the experiment, the sample was scraped flat into the sample slot. The emission current was 40 mA, with an acceleration voltage of 40 kV.

2.9. Thermogravimetry analysis (TGA)

TGA instruments (STA449F3, Netzsch, German) were used to analyze liposomes. The freeze-dried liposome sample was put into an aluminum dish and heated between 40 and 500 °C at a rate of 10 °C/min.

2.10. Differential scanning calorimeter (DSC)

A DSC instrument (DSC25, TA, USA) was used to investigate the thermal properties of freeze-dried liposomes using the approach of Zhao et al. (2024) with minor changes.

2.11. Stability evaluation

2.11.1. Ionic strength stability

The effect of ionic strength on liposome stability was investigated by adding NaCl at different concentrations (0, 0.05, 0.1, 0.2, 0.3, and 0.5 mol/L) (Li et al., 2022).

2.11.2. Storage temperature stability

Liposome sample solutions were preserved at 4 °C, 25 °C, and 37 °C for 28 days, respectively. During storage, the appearance and particle size of the samples were assessed every seven days. EE was measured at the end of storage (Tan et al., 2021).

2.12. In vitro simulated digestion

According to the methodology used in prior work, an in vitro simulated gastrointestinal model was created to demonstrate the effect of HA-LUT-lips on the release properties of luteolin (Tai et al., 2020). The model had three phases: the mouth (simulated saliva fluid, pH = 6.8), the stomach (simulated gastric fluid, pH = 2.0), and the small intestine (simulated intestinal fluid, pH = 7.0). A water bath that oscillated at 37 °C was used for the entire simulated digestive process. Prior to mixing, all liposomes and simulated digestive fluid should be preheated to 37 °C. The following was comprehensive in vitro simulated digestion process: Liposomes were combined with simulated saliva (1:1, v/v) and incubated for 10 min to simulate mouth digestion. To simulate gastric digestion, oral digestion was combined with simulated gastric fluid (1:1, v/v) and incubated for one hour. To simulate small intestinal digestion, stomach digestion was combined with simulated intestinal fluid (1:1, v/v) and incubated for two hours. It was important to point that the pH of gastric digestion needs to be brought down to 7.0 before combining with simulated intestinal fluid.

Simulated saliva fluid was formulated by adding NaCl (1.59 g), KCl (0.20 g), and mucin (0.60 g) to distilled water, with the final volume adjusted to 1 L. The simulated gastric fluid consisted of NaCl (2.00 g), concentrated HCl (7.00 mL), and pepsin (3.20 mg/mL) dissolved in distilled water to a total volume of 1 L. For the simulated intestinal fluid, K₂HPO₄ (6.80 g), NaCl (8.78 g), bile salts (5.00 g), and pancreatin (3.20 mg/mL) were added to distilled water and brought to a volume of 1 L.

2.13. Lipid oxidation

Liposomes were maintained out of the light for 28 days in an incubator set at 50 °C to test their oxidative stability. The content of hydroperoxide and malondialdehyde (MDA) in liposomes was measured.

2.14. Statistical analysis

The results of three separate, repeating experiments were reported as mean ± standard deviation (SD). SPSS software (version 26.0, SPSS Inc., Chicago, USA) was used to analyze the data. For statistical comparisons, the Duncan test and analysis of variance (ANOVA) were employed to identify significant differences (p < 0.05).

3. Results and discussion

3.1. Physicochemical characteristics

The EE of all liposomes is shown in Fig. 1A. Luteolin was found in the hydrophobic portion of liposomes and had a significant affinity for them. The EE of luteolin in LUT-lips was 63.62 ± 1.23 %, which was similar to previous research (Li et al., 2022). The location and configuration of luteolin within liposomes were linked to the encapsulation ability, and the thin hydrophobic bilayer of liposomes was mostly to blame for the poor EE (Pu et al., 2019). Luteolin exhibited stronger binding ability in hyaluronic acid encapsulated liposomes, which was positively correlated with hyaluronic acid concentration. The corresponding EE for 0.25, 0.50, 0.75, and 1.00 mg/mL HA were 68.91 ± 2.50 %, 74.04 ± 0.53 %, 86.92 ± 1.01 %, and 91.32 ± 0.66 %, respectively. The increase of EE in HA-LUT-lips was attributed to hyaluronic acid coating on the phospholipid bilayer surface, filling the gaps in liposomes and preventing leakage of luteolin from the hydrophobic core of liposomes.

Fig. 1.

Fig. 1

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The encapsulation efficiency (EE) (A), size and polydispersity index (PDI) (B), zeta-potential (C), and loading capacity (LC) (D) of LUT-lips and HA-LUT-lips with different HA concentrations (0.25, 0.50, 0.75, 1.00 mg/mL). Different letters indicate significant differences (p < 0.05).

Particle size, PDI, and zeta potential are crucial indicators for characterizing the uniformity and stability of liposomes. The size represents the average diameter, and PDI reflects the degree of dispersion. The smaller the PDI, the more uniform the distribution of liposomes (Huang, Song, et al., 2024). Fig. 1B displays the variations in liposome size and PDI with HA concentration. The particle size of LUT-Lips was 63.77 ± 0.33 nm, and the PDI value was 0.09 ± 0.01. The HA coating (ranging from 0.25 to 1.00 mg/mL) increased the particle size, with a size range of 134.20 to 230.37 nm, which was directly related to the concentration of HA. The increase in particle size upon HA coating was primarily due to the adsorption of hyaluronic acid molecules onto the surface of the liposomes, forming an additional layer around the phospholipid bilayer via hydrogen bonding and other non-covalent interactions (Wang et al., 2024). PDI generally varied between 0 and 1.0; However, exceeding 0.5 indicated a wide size distribution, with larger particles and aggregates (Lu et al., 2023). The PDI value of HA-LUT-lips ranged from 0.09 to 0.43. When the HA concentration was 1.00 mg/mL, the PDI increased to 0.43, reaching its maximum value. The increase in average diameter and PDI could be attributable to HA adsorption via the nanoscale size effect of liposomes. HA can cause the formation of an outer membrane on the liposome surface by physical absorption. Although the addition of luteolin expanded the average diameter distribution, the PDI value remained below 0.5, indicating that the dispersion of the encapsulated liposome suspension was generally uniform. The zeta potential reflects the surface charge of liposomes. An absolute value of zeta potential higher than 10 mV indicates the stability of liposomes (Tan et al., 2024). Luteolin molecules were neutral, while the zeta potential of unencapsulated liposomes was −7.65 ± 0.60 mV (Fig. 1C), which may be due to the dipolar tropism of the hydroxyl group of luteolin binding to the choline of lecithin, thereby increasing the surface charge of liposomes. As the concentration of HA increased (ranging from 0.25 to 1.00 mg/mL), the zeta potential of HA-LUT-lips varied between −14.63 mV and − 29.83 mV, demonstrating the effective encapsulation of HA on the surface of liposomes. The increase in absolute value indicated that HA had increased the electrostatic repulsion among liposomes, making them less likely to aggregate and enhancing the stability (Wang, Zhu, et al., 2025). As shown in Fig. 1D, the drug loading capacity (LC) of LUT-lips was 2.95 ± 0.26 %, while that of hyaluronic acid-coated liposomes (HA-LUT-lips) exhibited a significant increasing trend with rising hyaluronic acid concentration. The LC values corresponding to 0.25, 0.50, 0.75, and 1.00 mg/mL HA were 3.58 ± 0.13 %, 4.71 ± 0.13 %, 5.25 ± 0.25 %, and 6.45 ± 0.37 %, respectively. This concentration-dependent enhancement in drug loading was positively correlated with the thickness of the hyaluronic acid coating layer.

3.2. Morphology observation

3.2.1. TEM analysis

TEM displayed the morphologies of the liposomes (Fig. 2). The particle size range of liposomes without luteolin was 50–80 nm, while those encapsulated with luteolin were 100–130 nm, demonstrating the successful encapsulation of luteolin. However, the aggregation phenomenon of LUT-Lips was observed, which was attributed to the small electrostatic repulsion leading to the aggregation of liposomes. As the concentration of HA increased (0.25–1.00 mg/mL), the particle size range was 130–250 nm, which was confirmed by DLS measurements. Liposomes with HA had much bigger particle sizes than those without added HA, and a light-colored coating can be detected at the outer periphery of the liposomes, showing that the HA coating successfully formed a core-shell structure (Ahad et al., 2024). The dispersibility of liposomes was great between 0.25 and 0.75 mg/mL HA, with little aggregation, which may be due to the addition of HA increasing the electrostatic repulsion among liposomes. The addition of 1.00 mg/mL of HA caused a considerable increase in particle size and an unevener vesicle dispersion. The stoichiometric ratio of the interaction between HA and liposomes was particular. A HA concentration of 1.00 mg/mL may be higher than the maximum stoichiometric ratio, and too much HA may agglomerate and impair the liposome vesicles' ability to disperse. The results indicated that the microstructure of liposomes was barely affected by the moderate HA treatment, while excessive HA modification can affect the dispersibility of liposome particles. This occurrence was most likely caused by an increase in the amount of HA, which could promote interactions with liposomes, resulting in the loss of HA-LUT-lips. It has been claimed that guar gum-coated liposomes displayed similar behavior, with a thinner coating layer formed around the liposomes due to polysaccharide modification, indicating the flat adsorption of polysaccharides on the surface of vesicles (Pu et al., 2019).

Fig. 2.

Fig. 2

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The TEM images of liposomes (A), LUT-lips (B), 0.25 mg/mL HA-LUT-lips (C), 0.50 mg/mL HA-LUT-lips (D), 0.75 mg/mL HA-LUT-lips (E), and 1.00 mg/mL HA-LUT-lips (F).

3.2.2. AFM analysis

AFM was used to investigate the morphology and size of HA-coated and untreated liposomes (Fig. 3). The bare liposomes were spherical, small, and evenly distributed. LUT-lips were also spherical but had an obvious aggregation, with an average height of 35.5 nm. As HA concentration increased (0.25–0.75 mg/mL), liposomes remained spherical or disc-shaped, with smooth surfaces and uniform dispersion. This demonstrated that HA encapsulation can create the barrier, increasing the stiffness of vesicle structures and thereby inhibiting fusion and aggregation. The height of HA-LUT-lips increased from 45.79 nm to 72.80 nm, indicating successful encapsulation of HA on the liposomes. When coated with 1.00 mg/mL HA, the vesicles exhibited apparent agglomeration, low dispersion, and an uneven form. Excessive HA can cause vesicles to aggregate and reduce liposome dispersibility, both of which were in line with the TEM findings. According to previous research, chitosan-modified liposomes were bigger, taller, and more rigid than unmodified liposomes, which further altered their properties for drug release, digestion, and particle stability (Zhou et al., 2021).

Fig. 3.

Fig. 3

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The AFM images of liposomes (A), LUT-lips (B), 0.25 mg/mL HA-LUT-lips (C), 0.50 mg/mL HA-LUT-lips (D), 0.75 mg/mL HA-LUT-lips (E), and 1.00 mg/mL HA-LUT-lips (F).

3.3. Interaction of HA coating with the LUT-lips

3.3.1. FTIR analysis

FTIR analysis was used to assess the efficiency and interaction of HA coating on LUT-lips (Fig. 4A). Compared to bare lips, LUT-lips displayed characteristic peaks of luteolin, such as 1357, 1604, and 1656 cm−1 (Huang, Lu, et al., 2024; Zhang et al., 2020). For LUT-lips, the peak of -OH was found at 3407.60 cm−1. The interaction between hydrogen bonds in HA and LUT lips caused a noticeable shift in the hydroxyl peak from 3431.7 cm−1 (HA) and 3407.60 cm−1 (LUT-lips) to 3430.26 cm−1 (HA-LUT-lips) as the concentration of HA increased (Cheng, Wang, et al., 2024). Upon the addition of HA, the distinct peaks transition from 2854 cm−1 to 2855 cm−1, indicating the stretching vibrations of CH2 groups within the alkyl chains and a greater ordering of the phospholipid acyl chains (Huang, Song, et al., 2024). Additionally, the peak at 1740.44 cm−1 signified the stretching vibration of the C Created by potrace 1.16, written by Peter Selinger 2001-2019 O bond in the phospholipid bilayer. As the concentration of HA increased, the peak corresponding to the C Created by potrace 1.16, written by Peter Selinger 2001-2019 O tensile vibration shifted from 1740.44 cm−1 to 1739.96 cm−1. This shift pointed to alterations in the structure of the ester groups and significant hydration within the carbonyl region (Sun, Zhao, et al., 2025). This result suggested the formation of new hydrogen bonds between the -OH group of HA and the C Created by potrace 1.16, written by Peter Selinger 2001-2019 O group LUT-lips. Additionally, the peaks at 1091.51 cm−1 and 1246.27 cm−1 reflected the symmetrical and asymmetrical stretching vibrations of PO2− in the phospholipid bilayer. With rising HA concentration, these stretching vibration peaks transitioned from 1246.27 cm−1 and 1091.51 cm−1 to 1247.24 cm−1 and 1090.55 cm−1. Our results indicated that the incorporation of HA led to enhance hydration in the phospholipid head group region, as well as a more organized structure in the hydrocarbon tail region of the liposomes (Ren, Li, et al., 2024).

Fig. 4.

Fig. 4

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FTIR spectra (A), Raman spectra of LUT-lips and HA-LUT-lips in 400–2000 cm−1 (B) and 2700–3100 cm−1 (C), and XRD (D).

3.3.2. Raman spectra analysis

Raman spectroscopy is an effective multi-component quantitative analysis technique in which the form, shift, and intensity of absorption peaks correlate to the molecules vibrational. Raman spectroscopy serves as the most compelling proof of the lipid hydrocarbon chain architecture in liposomes. It captures alterations in both the trans and gauche configurations of these hydrocarbon chains (Wan et al., 2024). This study investigated the structural changes of HA-coated luteolin liposomes by observing Raman spectroscopy (Fig. 4 BCE). The C—H stretching vibration range (2800–3000 cm−1) and the C—C stretching vibration range (1000–1200 cm−1) were the two fundamental components of the molecular conformation of lipid bilayers. The distinct peak observed at 1094 cm−1 was linked to the gauche rotations occurring in the hydrocarbon chains, while the notable peaks at 1303 cm−1 and 1652 cm−1 were attributed to the C Created by potrace 1.16, written by Peter Selinger 2001-2019 O telescopic vibration and the angular vibration of CH2, respectively (Fan et al., 2023). The incorporation of hyaluronic acid (HA) progressively diminished the intensity of these peaks in HA-LUT-lips, suggesting that the hydrophilic region of HA interacted with the bilayer acyl chains of the liposomes, which lead to the lateral arrangement of the phospholipid hydrocarbon structures. Additionally, the gauche conformation of C—N within the liposomes was identified at 715 cm−1. As the concentration of HA increased, the corresponding peaks for the liposomes shifted from 715 cm−1 to 718 cm−1, indicating that choline groups maintained gauche conformations within the liposomal bilayer. The I715/I1300 ratio is an indicator for quantifying conformational changes in distorted heads (Li et al., 2022). The I715/I1300 ratio decreased in HA-LUT-lips (Table 1). This meant that the adsorption of HA by LUT-lips, as a form of unfolding coiled chains, caused significant structural changes in the twisted conformation between choline groups. I2891/I2850 values can be determined using the intensity values of two peaks at 2891 cm−1 and 2850 cm−1. The increase in I2891/I2850 values in HA-LUT-lips may be due to an increase in lateral stacking and a decrease in phospholipid bilayer fluidity (Song et al., 2022). These changes highlighted the fact that HA modification leads to a more ordered vesicle structure.

Table 1.

The structural parameters of LUT-lips and HA-LUT-lips deduced from Raman spectra.

Sample I715/I1300 I2891/I2850
LUT-lips 0.78 ± 0.02a 1.59 ± 0.05a
0.25 mg/mL HA-LUT-lips 0.69 ± 0.01b 1.61 ± 0.03a
0.50 mg/mL HA-LUT-lips 0.58 ± 0.01c 1.75 ± 0.01b
0.75 mg/mL HA-LUT-lips 0.73 ± 0.04b 1.95 ± 0.01d
1.00 mg/mL HA-LUT-lips 0.76 ± 0.02a 1.87 ± 0.02c
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3.3.3. XRD analysis

The crystalline state of luteolin liposomes coated and uncoated with HA was determined by an X-ray diffractometer. Fig. 4D shows that there were some characteristic absorption peaks of luteolin between 5 and 50° (2 θ = 14.1°, 15.7°, 21.3°, 25.3°, 28.4°), indicating that LUT was in a highly crystalline state. However, there were no obvious characteristic crystal peaks in LUT-lips, indicating that lut-lips were in an amorphous state. When HA was added, no crystallization peak was also observed in HA-LUT-lips, proving that they were still in an amorphous state (Gu et al., 2023). The width of XRD peaks was connected to the size of the crystal structure, and defective crystals typically had wider peaks. The peak of HA-LUT-lips was narrower than LUT-lips, which may indicate that the HA coating led to a more stable structure. Consistent with the study by Li et al. (2024), soybean oleosome-associated proteins coated LUT-lips also showed this trend.

3.4. Thermal stability

3.4.1. TG and DTG analysis

Thermogravimetric curves were used to investigate weight loss events involving chemical reactions or physical changes. Fig. 5A depicts the thermogravimetric curves for luteolin, HA, and all liposomes. The initial stage, occurring between 40 °C and 250 °C, exhibited the least weight reduction, mainly resulting from the removal of residual moisture and low molecular weight volatiles. The second stage occurred within the temperature range of 250 °C to 450 °C, accounting for the largest weight loss. Among them, luteolin, HA, LUT-lips, and HA-LUT-lips (0.25–1.00 mg/mL) all underwent weight loss transformation, with residual weights of 74.23 %, 45.01 %, 48.93 %, and 62.06–65.67 % (0.25–1.00 mg/mL), respectively. The lipid bilayer predominantly consisted of C, H, and O, which underwent carbonization at elevated temperatures to achieve minimal residual weight. Interestingly, the HA-LUT-lips had a greater residual weight compared to the LUT-lips, with the highest residual quantity observed at a concentration of 0.75 mg/mL HA. This suggested that the liposomes were more thermally stable during the coating process. HA-LUT-lips showed significantly less weight loss than LUT-lips at high temperatures, underlining HA's protective function. These findings supported the effective encapsulation of HA on the liposomes' surface. According to the DTG spectrum (Fig. 5B), the weightlessness region of LUT-lips was approximately 305.09 °C. However, the main weight loss regions corresponding to 0.25, 0.50, 0.75, and 1.00 mg/mL HA were transferred to 335.38 °C, 352.44 °C, 353.20 °C, and 335.37 °C, respectively, indicating an enhanced heat resistance of LUT-lips, with the highest thermal stability observed in HA coating at 0.75 mg/mL. The findings of DTG were consistent with the results of TG. Huang, Lu, et al. (2024) also discovered similar phenomena, where the LUT-lips coated with whey protein isolate exhibited significantly less weight loss and higher thermal stability.

Fig. 5.

Fig. 5

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TG (A), DTG (B), and DSC curves (C) of luteolin, HA, liposome, LUT-lips, and HA-LUT-lips.

3.4.2. DSC analysis

When heated between 25 °C and 250 °C, the DSC spectra of luteolin, HA, and all liposomes were recorded, as shown in Fig. 5C. Luteolin exhibited a distinctive peak at 30.58 °C and disappeared from the LUT-lips. The spectrum of LUT-lips revealed two distinct peaks (71.96 °C and 135.65 °C), demonstrating the transition of liposomes from gel to liquid crystal form, with a phase transition temperature of around 135.65 °C (Tan et al., 2024). After adding HA, the Tm value increased, and the Tm value of 0.75 mg/mL HA-LUT-lips was the highest, reaching 183.20 °C. This suggested that HA prevented some lipid molecules from going through the melting transition by delaying the phase shift from liposome gel to liquid crystalline.

3.5. Environment stability

3.5.1. Ionic strength stability

The size of all lipospmes under different ion strength conditions is shown in Fig. 6A. The average particle size of LUT-lips dropped from 70.01 ± 6.10 nm to 46.30 ± 5.87 nm as the NaCl content rose from 0 to 0.5 mol/L. When salt ion was between 0 and 0.2 mol/L, the average particle size of HA-LUT-lips exhibited a trend of first dropping and then increasing. The average particle size increased again when salt ion was between 0.2 and 0.5 mol/L. This phenomenon could be caused by variations in the electrostatic repulsion between particles as a result of changes in ion strength. Van der Waals forces and hydrophobic contacts between vesicles were thought to be overcome by electrostatic repulsion when salt ions were less than 0.2 mol/L, which decreased vesicle aggregation. Aggregation and fusion occurred when salt ions were between 0.2 and 0.5 mol/L because the electrostatic shielding effect reduced electrostatic repulsion. The measurement results of PDI values for LUT-lips showed that the dispersion of vesicles was good within the range of 0–0.3 mol/L. At 0.5 mol/L, the PDI value of LUT-lips was 0.56 ± 0.03, and vesicles was uneven (Fig. 6B). It was speculated that under high salt conditions, LUT-lips were unstable and exhibited aggregation. It was worth noting that although HA-LUT-lips of different concentrations had higher PDI with increasing NaCl concentration, except for 1.00 mg/ml, the rate of PDI increase of HA-LUT-lips was much slower than LUT-lips, indicating that HA coating can delay the aggregation phenomenon of LUT-lips. Our hypothesis was further supported by the zeta potential of HA-LUT-lips, which showed a decreasing trend. The fastest decline was observed at 1.00 mg/mL HA-LUT-lips, which went from −29.83 ± 0.23 mV to −21.77 ± 0.75 mV (Fig. 6C). Furthermore, there was a positive correlation between the rise in salt ion concentration and the decline in EE values of all liposomes (Fig. 6D). This might be because the liposomes' lipid bilayer membrane is compressed by stronger ions under osmotic pressure, causing structural damage and LUT leakage (Li et al., 2024). Under different ion strength conditions, the EE of HA-LUT-lips was higher than LUT-lips. Due to the addition of HA, a thicker interface layer may result in higher EE values.

Fig. 6.

Fig. 6

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Size (A), PDI (B), Zeta-potential (C), and EE(D) of LUT-lips and HA-LUT-lips at different ionic strength conditions.

3.5.2. Storage temperature stability

Fig. 7 illustrates the storage stability of all liposomes at 4 °C, 25 °C, and 37 °C for 28 days. The size of all liposomes increased as storage time rose and the alterations at 25 °C and 37 °C were more significant than at 4 °C (Fig. 7A-C). This was attributed to the fact that when stored at higher temperatures, phospholipid bilayers were prone to oxidation and particle aggregation, which affected the storage stability (Sepúlveda et al., 2021). However, in contrast to LUT-lips, the rate of increase in size of HA-LUT-lips decreased, indicating that HA coating can delay the agglomeration phenomenon of LUT-lips. Fig. 7D shows the EE of all liposomes at different temperatures on 28th day. The EE of LUT-lips at 4 °C was significantly higher than that at 25 °C and 37 °C, suggesting that enhanced luteolin leakage may result from phospholipids increased molecular mobility and oxidation rate at higher temperatures. At 4 °C, 25 °C, and 37 °C, the EE of HA-LUT-lips was higher than that of LUT-lips, demonstrating the effectiveness of HA coating in preventing luteolin leakage. The appearance confirmed the size and EE results (Fig. 7E). After 28 days of storage, liposomes were relatively transparent at 4 °C, while turbidity appeared at 25 °C and 37 °C. Compared with HA-LUT-lips, the color of LUT-lips was more yellow, indicating the leakage of luteolin. The results showed that HA-LUT-lips outperformed LUT-lips in terms of storage temperature stability.

Fig. 7.

Fig. 7

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Size of LUT-lips and HA-LUT-lips at 4 °C (A), 25 °C (B) and 37 °C (C) during storage. EE (D) and appearance (E) of LUT-lips and HA-LUT-lips at 4 °C, 25 °C and 37 °C on the 28th day.

3.6. In vitro release study in simulated digestion

The DLS results showed that during the simulated mouth stage (Fig. 8A), the size of LUT-lips and HA-LUT-lips remained practically unchanged. When the liposomes were subjected to gastric digestion, the size of LUT-lips increased from 63.71 ± 1.65 nm to 143.29 ± 6.13 nm. This phenomenon could be brought on by modifications to the gastric fluid's pH, composition, and component charge, which would cause aggregation and disintegration of a small number of particles. Under the environmental conditions of gastric fluid exposure, vesicles aggregate due to electrostatic shielding and ion-binding effects (Li et al., 2022). During the simulated small intestine phase, the size of LUT-lips increased from 143.29 ± 6.13 nm to 210.85 ± 4.80 nm, suggesting that pancreatic enzymes and bile salts broke the lipid bilayer structure. HA-LUT-lips also showed similar results, except for 1.00 mg/mL, the increase in particle size was smaller than that of LUT-lips, indicating that HA surrounded liposomes with a protective shell, lessening the harm they caused to gastric fluid and facilitating intestinal fluid digestion. Fig. 8B shows that the simulated mouth stage released less than 6 % of luteolin from HA-coated liposomes, or slightly more than 7 % from unencapsulated liposomes. Because of short digesting step and lack of specialized enzyme activity, mouth stage was not the primary liposome release location. The surface adsorption and mechanical breakdown of smaller fractions of liposomes were responsible for the majority of the luteolin released during this phase (Tai et al., 2020). When liposomes undergo gastric digestion, a faster release rate of luteolin was observed in LUT-lips. More than 30 % of luteolin was released by the end of the gastric phase (at a cumulative time of 70 min, after 10 min oral and 60 min gastric digestion). As the concentration of HA increased, the release rate of HA-LUT-lips gradually decreased (15–25 %), transporting more luteolin to the main digestive site (small intestine). As expected, the maximum release of luteolin occurred during the small intestine phase. After 190 min of digestion, more than 80 % of the encapsulated luteolin was released from LUT-lips, demonstrating the quickest release rate. HA-encapsulated liposomes continued to discharge at a slower rate than LUT-lips. In addition, the release rate of HA-encapsulated liposomes largely depended on the concentration of HA. The higher the quantity of HA, the slower the release of luteolin in liposomes, which corresponded to liposome stability and membrane fluidity. The sustained-release profile of HA-LUT-lips compared favorably with other polymer-coated luteolin delivery systems reported in the literature. For instance, soybean oleosome-associated proteins coated luteolin liposome showed a release of approximately 72 % after 3 h (Li et al., 2022). The HA-coated system, particularly at 0.50–1.00 mg/mL concentration, demonstrated a more sustained release pattern, which could be advantageous for targeted delivery to the intestine. Previous studies have also confirmed that chitosan coating enhanced the tolerance of liposomes to gastrointestinal stress, reducing the release of curcumin to 40–50 % (Tai et al., 2020). The results indicated that HA formed a strong protective barrier around liposomes, making the lipid bilayer harder and more resistant to digestion.

Fig. 8.

Fig. 8

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Size (A) and release rate of LUT (B) of LUT-lips and HA-LUT-lips during the vitro simulated digestion. Hydroperoxide (C) and MDA (D) of LUT-lips and HA-LUT-lips at 50 °C for 28 days.

3.7. Lipid oxidation of LUT-lips and HA-LUT-lips

Lipid oxidation has a negative impact on the quality of liposomes during storage. A decreased rate of lipid oxidation shows that liposomes are more oxidatively stable. In this study, the oxidative stability of liposomes was assessed by hydrogen peroxide and MDA at varied storage durations. As shown in Fig. 8CD, the levels of hydrogen peroxide and MDA in both LUT-lips and HA-LUT-lips showed a rising tendency with storage time at 50 °C. It was observed that the content of hydrogen peroxide gradually increased within the first 14 days and then sharply increased. When stored for 28 days, the concentration of lipid hydroperoxide in LUT-lips was 52.36 ± 2.87 mmol/L, while the concentrations of hydrogen peroxide in 0.25, 0.50, 0.75, and 1.00 mg/mL HA-LUT-lips decreased by 26.86 %, 37.00 %, 42.18 %, and 56.00 %, respectively. Similarly, at 28 days, a similar phenomenon was observed in MDA, which was due to the further decomposition of peroxides into aldehydes over time, thereby increasing MDA content (Yang et al., 2023). When stored for 28 days, the MDA concentration in LUT-lips was 28.01 ± 2.57 μmol/L, while the MDA concentrations in 0.25, 0.50, 0.75, and 1.00 mg/mL HA-LUT-lips were 20.76 ± 1.35, 18.84 ± 1.86, 16.15 ± 2.24, and 15.09 ± 2.60 μmol/L, respectively. This was attributed to the HA coating preventing lipid oxidation initiators from entering the oil phase.

4. Conclusion

In summary, our study provided a better understanding of the protective effect of HA-coated luteolin liposomes. HA may be wrapped flat on the surface of liposomes, filling the gaps in lipid rafts. Hydrogen bonding was crucial in preserving the physicochemical features and stability of HA-LUT-lips. HA can reduce the fluidity of liposome membranes and enhance bilayer orderliness. In addition, the HA coating improved the thermal stability of liposomes and increased the system stability of HA-LUT-lips. HA coating improved gastrointestinal release and resistance to lipid oxidation, thereby protecting the phospholipid bilayer structure of liposomes. The positive impact of HA encapsulation on liposomes can be used for transportation and encapsulation of luteolin to resist adverse environmental impacts in functional foods. Future prospects will focus on evaluating the in vivo bioavailability of this delivery system and exploring its practical application in functional foods and nutraceuticals.

CRediT authorship contribution statement

Le Cheng: Writing – original draft, Formal analysis, Data curation, Conceptualization. Ming Zhang: Writing – review & editing, Methodology, Investigation. Lin Dong: Data curation. Yifei Wang: Data curation. Jianguo Dong: Data curation. Fang Wu: Data curation. Chenyan Zheng: Data curation. Yumeng Ma: Data curation. Zihan Wang: Data curation. Ran Wang: Resources. Yixuan Li: Resources. Bing Fang: Writing – review & editing, Writing – original draft, Supervision, Funding acquisition, Conceptualization.

Declaration of competing interest

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

Acknowledgements

The work was supported by the National Key Research and Development Program of China (2022YFD2101003), the Cross-Innovation Open Project of Food Flavor and Health, Beijing Technology & Business University (FFHCI-2025061), and the 2115 Talent Development Program of China Agricultural University.

Data availability

Data will be made available on request.

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Associated Data

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Data Availability Statement

Data will be made available on request.

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