Research Advances for Protein-Based Pickering Emulsions as Drug Delivery Systems
Abstract
:1. Introduction
2. Protein-Based Particles Stabilized Pickering Emulsion
2.1. Influence of Protein-Based Particle Properties on Stabilization of Pickering Emulsions
2.2. Preparation and Modification of Protein-Based Particles for Pickering Emulsions
3. Stabilization Mechanism and Interfacial Properties of PPEs
3.1. Macroscopic Experimental Techniques on Interfacial Properties
3.2. Mesoscopic DPD Simulations for the Stabilization Mechanism
Interfacial Properties | Techniques | Advantages | Limitations | References |
---|---|---|---|---|
Visualization technology of morphology and the interfacial film | Optical microscopy | Simple operation, quick view of the structure and integrity | Hard to characterize the Pickering emulsion type and in-depth analysis of the morphology | [121] |
Scanning electron microscopy (SEM) | Observe the structure and morphology of the Pickering emulsion, assess the thickness of the Pickering shell formed by the solid particles, analyze in detail the adsorption behavior of particles | Cumbersome operating procedure, Pickering emulsion requires polymerization or freeze drying and gold/platinum coating | [39,122] | |
Confocal laser scanningmicroscopy (CLSM) | Reveal and structure and location of the interfacial adsorbed particles, analysis of the emulsion type, visual on the cross-sectional layer of a Pickering emulsion, 3D reconstruction | Tedious stain procedure dependent on target particles, continuous phase, dispersed phase and the staining agent | [123] | |
Transmitting electron microscopy(TEM) and Cryo-TEM | High definition and high resolution to detect the interfacial adsorbed particle, nanoscale monitoring of the cross-sectional image | Tedious operating procedure, needs special sample holder (e.g., copper grid) | [124] | |
Atomic force microscopy (AFM) | Measure the stiffness and strength of the interfacial shell based on tip-surface interaction and atomic-level resolution and detect the adsorbed particle, analysis of competitive adsorption and morphology | Complex sample preparation, limited to static films, special modifications to the probe tip may be required for stiffness and interface shell strength measurements, poor image quality | [125] | |
Brewster Angle Microscopy (BAM) | In situ dynamic monitoring of interface structures, no labeling required | Lower resolution (μm-scale), limited to air-water or oil–water interfaces | [126] | |
Interfacial tension | Pendant drop | High precision, real-time calculates γ via Young-Laplace equation based on droplet shape, suitable for static/dynamic adsorption monitoring | Sensitive to droplet size, requires optical calibration | [127] |
Wilhelmy plate | Measures vertical force on a platinum plate immersed in liquid to calculate γ via contact angle, simple operation, wide γ range | Susceptible to surface contamination | [128] | |
Microfluidics | High-throughput, monodisperse droplet control, combines droplet generation in microchannels with optical imaging to calculate γ | Expensive setup, precise flow control required | [129] | |
Interfacial adsorption mass and thickness | Centrifugation | Simple operation, separation of serum and cream layers, adsorbed mass derived from surface coverage and assumption of equilibrium partitioning | Underestimation for small droplets; lacks real-time dynamic monitoring | [130] |
Polystyrene Latex Particles | Indirect measurement via particle size changes due to adsorbed layers, quantifies thickness in model systems, mimics emulsion environments | Simplified models may not capture complex interfacial dynamics | [131] | |
Film Interferometry | High-precision in situ measurement, dynamic monitoring, interference patterns correlate with film thickness and refractive index | Requires transparent systems; complex optical alignment | [132] | |
Ellipsometry | Non-destructive, high resolution, real-time capability, Fresnel equations relate polarization changes to interfacial properties | Sensitive to surface roughness, requires complex modeling | [133] | |
Quartz Crystal Microbalance with Dissipation (QCM-D) | High sensitivity, real-time adsorption kinetics, structural insights, frequency (Δf) and dissipation (ΔD) shifts used to calculate mass and viscoelasticity | Expensive sensors, simplified models may ignore interfacial complexity | [106] | |
Interfacial rheology | Interfacial dilatational rheology (Langmuir Blodgett) | Investigate the dynamics of the adsorption process of particles at the interface (diffusion, penetration, recombination) and the viscoelastic modulus of the interface film (elastic modulus Ed, viscous modulus Ev) via Langmuir trough or pendant-drop methods | Limited frequency range, only applicable to low frequencies | [134] |
Interfacial shear rheology | Investigate the mechanical behavior of interfacial films under shear forces (elastic modulus, G′ viscous modulus, G″) to reveal intermolecular interactions and network structures, compatible with stress/strain-controlled rheometers, versatile testing modes | Low sensitivity for small deformations | [49] |
4. Applications of PPEs in Drug Delivery Systems
4.1. Drug Encapsulation
4.2. Controlled Release
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Preparation Approaches | Advantage | Limitation | Methods | Principles | Reference |
---|---|---|---|---|---|
Physical approaches | The common methods, simple operation, safe preparation, cheap cost and no new chemical formation | The particle structures stability dependent on environmental conditions, tends to dissociate into polymeric structures at the emulsion droplet interface upon addition, dilution or pH change | Mechanical methods | Micronization of particles via high shear, ball milling, sonication and supercritical fluid technology | [86] |
Isoelectric point methods | Proteins at the emulsion droplet interface aggregate to form nanoparticle as the pH is adjusted to the isoelectric point | [87] | |||
pH-cycle methods | In alkaline or acidic conditions, proteins first dissolve and then self-assemble into particles when the pH is adjusted to the level at which the protein becomes insoluble | [88] | |||
Antisolvent precipitation methods | Particle formation via supersaturation, nucleation, growth and agglomeration of the protein solutions by hydrogen bonding, electrostatic interaction and hydrophobic effects, including stepwise antisolvent precipitation methods and antisolvent coprecipitation methods | [89] | |||
Solvent evaporation methods | The water-insoluble proteins dissolve in a water-organic solvent mixture and spontaneously form particles by supersaturation as the organic solvent evaporates | [90] | |||
Heat-induced aggregation methods | Heat-treat proteins above denaturation temperature to cause denaturation, partial unfolding, and aggregation into particles, improve interfacial and emulsifying properties | [91] | |||
Non-electrostatic complexation methods | Mix two or more substances in aqueous protein solutions to form particles via non-electrostatic interactions, such as hydrophobic interactions and hydrogen bonding | [92] | |||
Chemical approaches | The covalently bonded particles show more stable shape, solubility, thermal stability, and emulsifying properties | Certain toxic crosslinkers compromise the safety of the particle within the human body | Ionic crosslinking | Mix polymers with opposite charges or use divalent ions (e.g., Ca2+) to shield negative charges, adjust pH between protein isoelectric points to induce self-assembly, form complex particles through electrostatic interactions | [93] |
Heat-induced disulfide crosslinking methods | Heat-treat proteins to denature and aggregate, reduce free sulfhydryl groups and form strong intraparticle disulfide bonds | [94] | |||
Aldehyde-induced covalent crosslinking methods | Use aldehyde agents (e.g., glutaraldehyde) to crosslink free amino groups in proteins, strengthen nanoparticle integrity, enhance storage and emulsion stability | [95] | |||
Genipin-induced covalent crosslinking methods | Use genipin to crosslink free amino groups in proteins or protein-polysaccharide conjugate, form stable particles with low cytotoxicity and long-term stability | [96] | |||
Polyphenol-induced covalent crosslinking methods | Use oxidized polyphenols to covalently modify protein nanoparticles, enhance interfacial behavior, oxidative stability, and emulsion resistance to digestion, improve emulsion stability and nutrient retention | [97] | |||
Biological approaches | High specificity, mild reaction conditions, and sustainable enzymes, improve functional properties and emulsion stability | Require further structural analysis to confirm particle formation and understand stabilization mechanisms, with limited enzyme types (e.g., transglutaminase, laccase) currently applied for crosslinking | Enzymatic methods | Use bottom-up methods to form nanoparticles by physical or ionic crosslinking followed by enzymatic covalent crosslinking, or use top-down methods to crosslink proteins into gels and mechanically break them into nanoparticles for Pickering emulsion stabilization | [98] |
Source of Protein | Type of Protein | Preparation Method | Emulsification Quantitative Parameters | Reference |
---|---|---|---|---|
Vegetable protein | Zein | Antisolvent precipitation | The Pickering emulsion was stable for 10 days at 1.5 wt% particle concentration and 50% oil content at room temperature. | [71] |
Soy protein | pH-induced crosslinking | Emulsions with 1.0–3.5 wt% nanoparticle concentrations and 50–70% oil fractions were stable at 4 °C for 20 days. | [102] | |
Peanut protein | Electrostatic adsorption | Emulsion stabilized with peanut protein complex (containing 0.35 g/100 mL cellulose nanocrystals) exhibited good stability with low creaming index at 30% oil fractions after 30 d storage. | [103] | |
Lupin protein | pH-induced precipitation | Heating greatly improved the emulsification performance of protein particles at high concentrations (>3%, w/v), and the emulsions were highly stable over 14 days storage. At a 0.5% protein concentration, it was not sufficient to stabilize the droplets. | [91] | |
Gliadin | Antisolvent precipitation | Stabilization of an O/W emulsion at a low concentration (0.1%, w/v), showed the greatest resistance to coalescence and the most reduction in mean particle diameter over a 30-day storage period. | [104] | |
gluten protein | Antisolvent precipitation | Emulsions with 4% glycosylated gluten nanoparticles and 40% oil-water volume showed the best thermal and storage stability (30 d). | [105] | |
Animal protein | β-lactoglobulin | Electrostatic interaction (polysaccharide–protein complexes) | At a controlled oil/water volume ratio of 1:9, concentrations of 0.8 wt% to 1.5% showed storage stability for up to 28 d, while the most severe creaming occurred in the emulsion stabilized by 0.2–0.8 wt% complexes. | [106] |
Casein | Glutaraldehyde covalent modification | Emulsions showed low instability index values, consistently below 0.2, indicating minimal aggregation or flocculation | [107] | |
Ovalbumin | Acid-heat modification | Oleogel-based Pickering emulsions at low concentrations (10 or 20 mg/mL) displayed ultra stability over 90-day storage and outstanding freeze-thaw stability. | [108] |
Natural Substances | Advantage | Principles | Preparation Method | Application | Reference |
---|---|---|---|---|---|
Protein-polysaccharide | Enhance hydrophilicity, interfacial properties and emulsion stabilityImprove emulsification, foaming, solubility and surface activity | Glycosylation of protein particles with polysaccharide via Maillard reaction between the reducing carbonyl group of the carbohydrate and the free amine group of the protein | Covalent bonding | WPI-Dextran (DX) conjugate microgel particles stabilize Pickering emulsion via Maillard reaction, delaying interfacial gastric proteolysis | [100] |
Modification of protein by non-covalent interactions with polysaccharide (e.g., electrostatic, hydrophobic, hydrogen bonding, van der Waals) to form soluble coacervates or insoluble aggregates | Non-covalent mediated | ZN-CS particle-stabilized Pickering emulsion delivery of quercetin, improving encapsulation efficiency and oral bioavailability | [109] | ||
Protein-protein | Improve interfacial absorption and emulsion stability, increase storage modulus and viscosity | Fabricate protein-protein complex particles by assembling oppositely charged proteins via electrostatic interactions, hydrogen bonds, and hydrophobic interactions under low ionic strength, enhance solubility and stability through pH-shifting or enzymatic crosslinking | Electrostaticinteraction | Zein-propylene glycol alginate-whey protein microgel particles stabilized Pickering emulsion for delivery of β-carotene, improving the photothermal stability and storage stability, delaying the lipolysis during gastrointestinal digestion | [110] |
Protein-phenolic | Enhance hydrophilicity, thermal stability, antioxidant activity, and emulsion stability, prevent protein aggregation | Fabricate protein-phenolic complex/composite particles by forming covalent bonds (via oxidation and nucleophilic reactions) or non-covalent interactions (e.g., hydrogen bonding, van der Waals forces) | Electrostaticinteraction | Pea protein-proanthocyanidin complex particles held together by hydrogen bonding, stabilized Pickering emulsion for proanthocyanidins delivery, increasing the storage stability | [101] |
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Deng, L.; Liao, J.; Liu, W.; Liang, X.; Zhou, R.; Jiang, Y. Research Advances for Protein-Based Pickering Emulsions as Drug Delivery Systems. Pharmaceutics 2025, 17, 587. https://doi.org/10.3390/pharmaceutics17050587
Deng L, Liao J, Liu W, Liang X, Zhou R, Jiang Y. Research Advances for Protein-Based Pickering Emulsions as Drug Delivery Systems. Pharmaceutics. 2025; 17(5):587. https://doi.org/10.3390/pharmaceutics17050587
Chicago/Turabian StyleDeng, Long, Junqiu Liao, Weiqi Liu, Xiaoxiao Liang, Rujin Zhou, and Yanbin Jiang. 2025. "Research Advances for Protein-Based Pickering Emulsions as Drug Delivery Systems" Pharmaceutics 17, no. 5: 587. https://doi.org/10.3390/pharmaceutics17050587
APA StyleDeng, L., Liao, J., Liu, W., Liang, X., Zhou, R., & Jiang, Y. (2025). Research Advances for Protein-Based Pickering Emulsions as Drug Delivery Systems. Pharmaceutics, 17(5), 587. https://doi.org/10.3390/pharmaceutics17050587